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The renal (myo-) fibroblast: A heterogeneous group of cells


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Several studies have demonstrated that mesenchymal stem cells have the capacity to reverse acute and chronic kidney injury in different experimental models by paracrine mechanisms. This paracrine action may be accounted for, at least in part, by microvesicles (MVs) released from mesenchymal stem cells, resulting in a horizontal transfer of mRNA, microRNA and proteins. MVs, released as exosomes from the endosomal compartment, or as shedding vesicles from the cell surface, are now recognized as being an integral component of the intercellular microenvironment. By acting as vehicles for information transfer, MVs play a pivotal role in cell-to-cell communication. This exchange of information between the injured cells and stem cells has the potential to be bi-directional. Thus, MVs may either transfer transcripts from injured cells to stem cells, resulting in reprogramming of their phenotype to acquire specific features of the tissue, or conversely, transcripts could be transferred from stem cells to injured cells, restraining tissue injury and inducing cell cycle re-entry of resident cells, leading to tissue self-repair. Upon administration with a therapeutic regimen, MVs mimic the effect of mesenchymal stem cells in various experimental models by inhibiting apoptosis and stimulating cell proliferation. In this review, we discuss whether MVs released from mesenchymal stem cells have the potential to be exploited in novel therapeutic approaches in regenerative medicine to repair damaged tissues, as an alternative to stem cell-based therapy.
Histological features of renal fi brosis in rats. The kidney tubulointerstitium of a healthy rat is depicted in ( A ). Note the narrow interstitial space with capillaries and very few inconspicuous cells (arrows). In ( B ) a rat kidney 5 days after UUO, a widely used model of renal fi brosis is shown. The altered tubulointerstitium shows all of the typical features observed in renal fi brosis: expansion of ECM (asterisk), altered tubular phenotype (arrowhead points to a mitosis in a tubular cell of a dilated and partly atrophied tubule) and in fl ammatory in fi ltrates (arrow). These changes closely resemble the fi brosis observed in renal biopsies of patients with kidney diseases. Exaggerated deposition of ECM is shown on the example of type I collagen immunohistochemistry in healthy ( C ) and fi brotic rat kidneys ( D ). In normal kidneys, very fi ne focal expression is found in the interstitium (arrowhead in C) and around arterioles (a, arrow in C), whereas its expression is signi fi cantly increased during fi brosis (arrow and arrowhead in D). In UUO, no expression of collagen I is found in the glomeruli (glo). Expression of a widely used marker for myo fi broblasts, α SMA, is shown for normal ( E ) and fi brotic kidneys ( F ). In normal kidneys, α -SMA is expressed only by VSMCs of arteries and arterioles (a). In fi brosis, a striking de novo expression in the interstitium is found (arrowhead in F). Note that tubular cells do not express α -SMA (arrows in F) and no expression in glomeruli (glo) is found. A marker for mesenchymal cells, vimentin, is shown for normal ( G ) and fi brotic kidneys ( H ). In normal kidneys, vimentin is strongly expressed in glomeruli (glo) by podocytes, mesangial cells and parietal epithelial cells as well as in arteries by VSMCs and arterioles (a) and interstitial fi broblasts (arrowhead in G) but not by tubular cells (arrow in G). During fi brosis, expansion of interstitial vimentin- positive cells is obvious (arrowhead in H). Note the de novo expression of vimentin in single and clusters of injured tubular cells (arrows in H). PAS, periodic acid-Schiff staining, original magni fi cations ×400.
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Editorial Review
The renal (myo-)broblast: a heterogeneous group of cells
Peter Boor1,2,3 and Jürgen Floege1
Division of Nephrology, RWTH University of Aachen, Aachen, Germany,
Institute of Pathology, RWTH University of Aachen,
Aachen, Germany and
Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia
Correspondence and offprint requests to: Peter Boor; E-mail:
Renal brosis is a central pathological process in kidneys
of patients with chronic kidney disease (CKD). Identi-
cation of effective treatments that halt or reverse brosis
would be benecial for most, if not all, CKD patients.
Key to this is an understanding of brogenesis, including
the principal responsible cells, the renal broblasts. It is
in part due to their inconspicuous appearance that it was
believed that there might not be much more to a broblast
than a simple interstitial mesenchymal cell which makes
up the organ stroma. The so-called renal broblastsare a
heterogeneous population of mesenchymal cells with
various essential functions during kidney development
and in adult life. Still, remarkable uncertainties exist in
the nomenclature of renal mesenchymal cellsor renal
broblastsand molecular characterization remains poor.
The embryonic origin of broblasts is unclear as well,
although some studies point to a neural crest origin of
these cells. The renal myobroblasts appear de novo in
renal brosis, originating from renal broblasts. Myobro-
blasts most likely represent a stressed and dedifferentiated
phenotype of broblasts. We have only just begun to
appreciate that renal broblasts are anything but simple
renal interstitial cells.
Keywords: kidney development; origin of broblasts; renal brosis;
renal stroma; markers
Chronic kidney disease (CKD), dened as impaired renal
function for 3 months or longer, is often asymptomatic,
which delays the diagnosis of CKD until advanced stages
of disease. The prevalence of CKD has reached pandemic
proportions and some epidemiological studies have shown
that up to 10% of the worlds population is affected [1].
With increases in the aged population, the number of CKD
patients is expected to rise even further in the future. CKD
is a strong and independent risk factor for cardiovascular
morbidity and mortality and the risk increases with each
CKD stage. In so-called developing countries, where
access to renal replacement therapies is limited or does not
exist at all, the nal stage of CKD most often equates to
death. It is estimated that >1 million patients die per year
as a result of the nal CKD stage, i.e. end-stage renal
disease. In developed countries, both renal replacement
modalities, dialysis and renal transplantation, are available,
but they are extremely expensive and are associated with a
substantial reduction in the quality of life and life expect-
ancy of the patients. The worldwide cost of renal replace-
ment therapy is estimated to be $1 trillion [1].
Essentially, all chronic renal diseases, but also re-
peated or serious acute insults, inevitably lead to renal
brosis. The underlying and principal pathological
nding in the kidneys of CKD patients is renal brosis
[24]. The importance of brosis, be it glomerulo-
sclerosis or tubulointerstitial brosis, is illustrated by its
close correlation with the decline in renal function. It
has been reported that interstitial brosis correlates
more closely with the decline in renal function than
glomerulosclerosis [5], but that may simply reect our
inability to accurately quantify glomerulosclerosis in a
renal biopsy with limited numbers of glomeruli.
Fibrosis is a fundamental biological process, and an es-
sential and benecial step in the course of tissue repair
and regeneration. It is possible that focal or initial brosis
is a benecial process in kidney disease, since it might
support the mechanical stability of the injured organ and
encapsulate injured nephrons [2]. Nevertheless, sustained
and uncontrolled brosis becomes pathological, since the
functional tissue is ultimately replaced by permanent scar
tissue. Such scars disrupt normal organ structure and
thereby hinder the possibility for regeneration and normal
organ function. The key characteristics of renal brosis
are the extensive deposition of the extracellular matrix
(ECM) and expansion of the broblast population. Renal
brosis is often, if not always, associated with monocytic
inammatory inltrates and phenotypic alterations or loss
of resident renal cells, e.g. tubular and capillary endo-
thelial cells. The histological appearance of these changes
is shown in Figure 1.
Given its almost universal appearance in CKD, renal
brosis, in particular interstitial brosis, is an excellent
treatment target. Within the brotic process, a prime
target for therapy is the principal cell responsible for the
exaggerated production and deposition of ECM, i.e. the
renal broblast.
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Fig. 1. Histological features of renal brosis in rats. The kidney tubulointerstitium of a healthy rat is depicted in (A). Note the narrow interstitial
space with capillaries and very few inconspicuous cells (arrows). In (B) a rat kidney 5 days after UUO, a widely used model of renal brosis is
shown. The altered tubulointerstitium shows all of the typical features observed in renal brosis: expansion of ECM (asterisk), altered tubular
phenotype (arrowhead points to a mitosis in a tubular cell of a dilated and partly atrophied tubule) and inammatory inltrates (arrow). These changes
closely resemble the brosis observed in renal biopsies of patients with kidney diseases. Exaggerated deposition of ECM is shown on the example of
type I collagen immunohistochemistry in healthy (C) and brotic rat kidneys (D). In normal kidneys, very ne focal expression is found in the
interstitium (arrowhead in C) and around arterioles (a, arrow in C), whereas its expression is signicantly increased during brosis (arrow and
arrowhead in D). In UUO, no expression of collagen I is found in the glomeruli (glo). Expression of a widely used marker for myobroblasts, α-
SMA, is shown for normal (E) and brotic kidneys (F). In normal kidneys, α-SMA is expressed only by VSMCs of arteries and arterioles (a). In
brosis, a striking de novo expression in the interstitium is found (arrowhead in F). Note that tubular cells do not express α-SMA (arrows in F) and
no expression in glomeruli (glo) is found. A marker for mesenchymal cells, vimentin, is shown for normal (G) and brotic kidneys (H). In normal
kidneys, vimentin is strongly expressed in glomeruli (glo) by podocytes, mesangial cells and parietal epithelial cells as well as in arteries by VSMCs
and arterioles (a) and interstitial broblasts (arrowhead in G) but not by tubular cells (arrow in G). During brosis, expansion of interstitial vimentin-
positive cells is obvious (arrowhead in H). Note the de novo expression of vimentin in single and clusters of injured tubular cells (arrows in H). PAS,
periodic acid-Schiff staining, original magnications ×400.
3028 Nephrol Dial Transplant (2012): Editorial Review
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What are broblasts and myobroblasts?
At rst glance, the term broblast seems a straightforward
one. Fibroblasts are mesenchymal cells residing and
embedded in the ECM or stroma of connective tissues or
organs [6]. Several general denitions exist for broblasts,
e.g. a connective-tissue cell of mesenchymal origin that
secretes proteins and especially molecular collagen from
which the extracellular brillar matrix of connective
tissue forms (
broblast). Fibroblasts are characterized by light
microscopy as elongated, spindle- or stellate-shaped cells
with rather pale cytoplasm and oval (or round) nuclei.
The rst description of these cells dates back to the 1850
70s by Virchow [7,8]. Ultrastructurally, renal broblasts
have an abundant endoplasmatic reticulum, collagen-
secreting granules and processes forming contacts to other
cells and basement membranes, including tubular, endo-
thelial and dendritic cells [9]. These cells can be isolated,
cultured and expanded in vitro, where the cells show a
morphology similar to the one in vivo.
The term broblast, although widely used, is not
completely correct. A blastdenotes a cell with stem cell
features or in an activated state. The correct term for a
resting, differentiated broblast should be brocyte, as is
the case for other mesenchymal cells, e.g. chondrocytes
or osteocytes. However, the term brocyteis not used to
describe resting broblasts. Instead, it is used for circulat-
ing progenitors of broblasts expressing haematopoietic
markers and collagen (e.g. CD45
, CD33
, col1
11]. For clarity, in this review, we will use the term bro-
blast for both resting and activated broblasts, and the
term brocyte for the circulating precursor of broblasts.
The term myobroblast was rst used some 100 years
after the term broblast was introduced, when in 1971
Majno et al.[12] described phenotypic alterations of
broblasts towards a smooth muscle-like phenotype in
contracting dermal wound granulation tissue. This also
remains the main denition of a myobroblast today: a
broblast that has developed some of the functional and
structural characteristics (as the presence of myolaments)
of smooth muscle cells (
medical/myobroblast). A fully developed myobroblast
is dened as a cell with a light-microscopic appearance
similar to that of broblasts (i.e. spindle- or stellate-
shaped cells with oval nuclei and pale cytoplasm) that
expresses vimentin, α-smooth muscle actin (α-SMA) and
extra-domain A of bronectin (ED-A bronectin) but not
smooth muscle myosin or desmin [13,14]. An important
part of the denition, however, is based on the ultrastruc-
ture. A fully differentiated and mature myobroblast should
have a prominent endoplasmatic reticulum, prominent Golgi
apparatus and collagen-secreting granules, peripheral myo-
laments and gap and bronexus junctions (the latter being
connections of intracellular myolaments with extracellular
bronectin) [14]. As in most studies of renal brosis, in the
following section, we will use the term myobroblast
for renal interstitial cells positive for α-SMA, i.e. not
necessarily mature myobroblasts.
Until now, no markers have been found that are
expressed specically and exclusively on broblasts or
that would label all broblasts (Table 1). This is not a
specic problem of broblasts but of mesenchymal cell
biology in general. For example, a denition of mesench-
ymal stem cells involves the expression and lack of
expression of a number of surface markers (e.g. CD29,
CD44, CD73, CD90, CD105 and CD31, CD33, CD11b,
CD45, respectively) rather than any specic markers [15].
Mesenchymal stem cells, also denoted mesenchymal
stromal cells, indeed bear some similarities to broblasts.
Some studies suggested that these cells reside not only in
bone marrow but also in other organs, especially in the
perivascular space (or niche) [16]. Furthermore, broblasts
Table 1. Renal expression of some of the most widely used markers
of mesenchymal cells
Marker (human gene
Expression Function
Vimentin (Vim) VSMCs Component of
cytoskeleton (class III
intermediate lament of
the desmin group)
Mesangial cells
Injured tubuli
Desmin (Des) VSMCs Component of
cytoskeleton (muscle-
specic class III
intermediate lament of
the desmin group)
α-SMA α-smooth
muscle actin (Acta2)
VSMCs Major actin isoform of the
contractile cell apparatusMyobroblasts
mesangial cells
derived growth factor
VSMCs Cell membrane receptor
for platelet-derived growth
factor (PDGF)BB and
Mesangial cells
S100A4 S100 calcium-
binding protein A4
(S100A4) also termed
protein 1 (FSP-1)
VSMCs Cytoplasmic and nuclear
protein, member of the
S100 family of proteins
with calcium-binding
motifs and broad cellular
Tubular cells
CD73 ecto-5-
nucleotidase [5-NT]
Fibroblasts Cell membrane enzyme
involved in conversion of
extracellular nucleotides to
Tubular cells
As can be seen, using one single marker does not allow a distinction
between various cell types. It should be mentioned that it is not yet clear
whether these markers are expressed in all cells of a certain type (i.e.
broblasts or pericytes) and to what extent the expression might change
during phenotypic alteration. See also Figure 1.
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isolated from brotic kidneys were shown to be hetero-
geneous and a certain population exhibited some stem cell
features, such as clonal expansion or formation of 3D struc-
tures [17]. It is possible that some of the renal broblasts,
in particular perivascular broblasts, might be resident me-
senchymal stem cells. To distinguish between broblasts,
brocytes, monocytes and macrophages in human tissue,
their histological localization together with the analysis of
at least three to four markers was necessary [18].
In healthy kidney cortex, apart from vascular smooth
muscle cells (VSMCs), virtually no expression of α-SMA
can be found. In renal brosis, a striking up-regulation is
observed (Figure 1). This marker seems to be specic
enough to distinguish myobroblasts from other mesench-
ymal cells if analysed strictly in the peritubular space
(Table 1and Figure 1). However, α-SMA is not expressed
by all myobroblasts and some α-SMA-negative cells can
be myobroblasts [19]. The expression of other markers
of myobroblasts, e.g. of ED-A bronectin, has not yet
been used extensively, although it is expressed in an
almost de novo fashion in human interstitial brosis [20].
S100A4, also termed broblast-specic protein 1 (FSP-1),
was shown to be expressed by leukocytes, which limits its
use as a marker for broblasts in renal brosis (Table 1)
[9]. Other markers for renal broblasts include cadherin 9
[21] while some still need to be examined, e.g. broblast
activation protein. The lack of specicmarkersledtoa
denition per exclusion. A renal broblast should not
express markers of epithelial (e.g. cytokeratins), endothelial
(e.g. von Willebrand factor), vascular (e.g. SM-22) and
inammatory cells (e.g. CD45), a denition especially rel-
evant for cell characterization in in vitro studies. Such a
denition obviously does not differentiate between the
various populations of renal mesenchymal cells (Table 1).
The identication and characterization of mesenchymal
cells using immunohistological markers remains poor, as
was shown for myobroblasts and pericytes [13,22]. At
present, the best way to distinguish between these cell
types is via ultrastructural analyses [13,22]. This is,
however, not feasible in our dailyexperimental studies.
Using collagen Iα1 promotor-driven green uorescent
protein (GFP)-expressing reporter mice, it was found that
in brosis induced by unilateral ureter obstruction (UUO)
75% of the GFP-positive interstitial cells also expressed
α-SMA [23]. Similarly, other studies showed that,
depending on the stage of experimental brosis, renal in-
terstitial broblasts vary in their phenotype when assessed
by vimentin and α-SMA (co-) expression [23]. These
studies suggested that, especially in renal brosis, various
phenotypes or subtypes of broblasts and myobroblasts
exist. This is well in line with the notion that broblasts
are a heterogeneous population of cells not only between
different organs but also within a given organ [2427].
What do renal broblasts do?
The best established and most likely major role of bro-
blasts is ECM production. Fibroblasts are essential in
shaping the structure of organs, providing structural and
mechanical support. On the basis of localization and ultra-
structure, it seems plausible that renal broblasts are
involved in the production of basement membranes of
tubules and capillaries and transmit mechanical and
biochemical signals between these structures. This might
indicate a pericyte-like and neuronal-like function of
broblasts (regarding the latter point, see the section con-
cerning the embryonic origin of broblasts). A role of
broblasts in the control of microcirculation is also sup-
ported by the expression of certain molecules affecting
haemodynamics, such as ecto-5-nucleotidase (CD73) or
soluble guanylyl cyclase (cGC) [9].
Renal broblasts are the major producers of erythro-
poietin (EPO) [2830]. Supporting the idea of renal bro-
blasts as a heterogeneous group of cells, a recent study
showed that <20% of renal broblasts produce EPO [31].
It is not yet clear why a certain subset of interstitial bro-
blasts is the major source of EPO and thereby the major
regulator of erythropoiesis for the whole organism. In
renal brosis, broblasts reduce or even lose their ability
to produce EPO, which is the major cause of renal
anaemia [31]. In vitro broblasts from healthy kidneys
express EPO mRNA, whereas myobroblasts do not.
Stimulation of these myobroblasts in vitro with various
factors, e.g. neurotrophins, brain-derived neurotrophic
factor, hepatocyte growth factor or lower concentrations
of dexamethasone is able to restore EPO production [31].
The localization of broblasts in the interstitium, i.e.
the space in which the transport of uids and solutes
between tubules and capillaries takes place, implicates a
potential role in this process as well. In particular, this was
suggested for medullary broblasts. These cells can con-
tract in response to vasoactive substances and peptides, e.g.
prostaglandin E
or atrial natriuretic peptide [32,33].
As in other organs like dermis or lymph nodes
[24,34], broblasts interact with immune cells, in particu-
lar with resident dendritic cells and macrophages [35]. In
renal brosis, the interaction between the expanded popu-
lation of myobroblasts and inltrating inammatory cells
is most likely reciprocally inuenced by each other. For
example, inltrating macrophages in brosis express
platelet-derived growth factor (PDGF)-C, which induces
chemokine expression in broblasts, thereby further
augmenting inammatory inltrates [36]. To date, there
exist only few data on the interaction of immune cells and
broblasts in healthy and diseased kidneys. This eld de-
serves further attention, given the potential immunomodu-
latory function of broblasts [37].
It is possible that renal broblasts also have other func-
tions, which are not yet known. A subset of medullary
interstitial broblasts has lipid inclusions (vitamin
A-storing granules). These cells bear some similarities to
hepatic stellate cells, but the relevance of these cells in
the kidney is unclear [38,39]. It has been suggested that
these particular cells express a protein specic for acti-
vated hepatic stellate cells, the cytoglobin/stellate-cell
activation-associated protein (Cypg/STAP) [39]. Cypg/
STAP-expressing cells signicantly accumulate in exper-
imental renal brosis but do not fully co-localize with
α-SMA [39].
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The functions of the various renal broblast subsets
still remain to be characterized.
What is the embryonic source of renal broblast?
During mammalian embryogenesis, the later kidney,
termed metanephros, is formed from the ureteric bud and
metanephric mesenchyme (also termed metanephrogenic
mesenchyme or metanephrogenic blastema), both deriv-
ing from the intermediate mesoderm [40] (Figure 2). The
structures induce each other, i.e. the ureteric bud induces
the condensation of the metanephric mesenchyme and
induces glomerulo- and tubulogenesis. On the other hand,
the metanephric mesenchyme induces branching of the
ureteric bud and the formation of the collecting ducts.
The origin and development of the renal interstitium,
often called renal stroma, is less well understood. In the
following section, we will often use the term interstitium
(or stroma) referring to mesenchymal stromal cells but not
other stromal elements such as capillaries, vasculature or
resident inammatory cells [41]. Some uncertainties in
the denitions exist in the embryonic kidney as well; the
precise denition of what all comprises the term renal
stromais not completely clear [42].
The embryonic origin of the renal stroma, i.e. renal
broblasts, is still largely unknown. Several possible
sources exist (reviewed in [33,42,43]): rst, it might
arise from the metanephric mesenchyme itself along with
tubulogenesis. Second, it might arise from the uninduced
intermediate mesenchyme in which the developing struc-
tures are embedded. Third, it might be derived from
different structures, e.g. the neural crest. And nally,
given the heterogeneous nature of broblasts, it is poss-
ible that these cells might be derived from more than one
of the aforementioned origins (Figure 2). The primary in-
terstitium of the developing kidney was shown to be dis-
tinct from the condensed metanephric mesenchyme (and
of course of the ureteric bud). These differences are both
morphological and molecular. Compared with condensed
metanephric mesenchyme, the primary interstitium was
shown to express tenascin, glycolipid disialoganglioside
and, in particular, the winged helix transcription
factor Foxd1 (formerly termed BF-2) [33,41,44,45]. As
all structures develop, the primary interstitium forms
the progenitor population for the mature cortical and
medullary interstitium. The latter is characterized by the
appearance of interstitial cells with lipid inclusions
(vitamin A-storing cells) [33,42].
Descriptive studies showed that embryonic stromal
cells express neuronal markers [46,47]. This suggested
an extrarenal neural crest origin of renal broblasts,
recently supported by an intriguing study using reporter
mice [31]. What is the neural crest? Arising from the
neural tube, the neural crest is a multipotent and migratory
cell population that appears transiently during embryogen-
esis. Various cells and tissues develop from the neural
crest, e.g. smooth muscle cells, melanocytes or peripheral
glial cells and neurons. In the aforementioned study, to
mark and follow the cells of neural crest origin, the pro-
moter for myelin protein zero (P0) was used [31]. P0 is
expressed in the neural crest but not in the developing or
adult kidney [31]. The marked cells were interstitial,
showed no expression of inammatory, dendritic or endo-
thelial cell markers, overlapped nearly completely with
PDGFR-βexpression and they also partly co-expressed
Foxd1, i.e. they appeared to be renal broblasts. In renal
brosis, these cells were the main, if not the only, source
of myobroblasts. Using other neural crest reporter mice
(Wnt-1 promotor), migration of neural crest cells to the
developing kidney was also observed. However, these
cells remained in a capsule-like fashion in the early stages
of the metanephric kidney and largely disappeared there-
after with only very few positive intrarenal cells remain-
ing [48]. In mice with a neural crest defect (Splotch-
decient mice) no expression of neural crest markers in
metanephros was observed and histologically these
kidneys and their interstitium were normal-appearing
[48]. This might suggest that there are various embryonic
sources of renal stroma. It should be mentioned that in
contrast to the aforementioned study [31], the expression
of P0 in mature murine podocytes and interstitial endo-
thelial cells was observed [49]. Taken together, the origin
of renal broblasts still remains to be claried. But the
possible neuronal origin of these cells could facilitate
further studies of biology and present novel roles of renal
What is the role of the stroma cells in kidney develop-
ment? Similar to the reciprocal interactions between the
ureteric bud and metanephric mesenchyme, reciprocal
interactions between interstitial cells and the ureteric bud
and evolving tubules have been suggested [33,42,50].
The retinoic acid receptors (RARαand RARβ
, involved
in vitamin A signalling), broblast growth factor 7 (FGF-7)
and bone morphogenic protein 4 (BMP-4) are all expressed
in embryonic stromal cells and are essential for normal
ureteric bud development and branching [42]. Stromal
cells have also been suggested to play a role in nephro-
genesis [33,42]. Foxd1-decient mice lacking the stromal
progenitors (Figure 2) develop only very few nephrons
compared with wild-type littermates [45].
The molecules driving the development of renal
stromal cells are largely unknown. To date, only some of
the factors have been described to be important in the
development and survival of embryonic stroma. These
include PDGF receptor αligands, PDGF-A and PDGF-C,
BMP-7 and molecules of the renin-angiotensin system
Future studies focusing on the origin and clues for the
development of renal stroma, i.e. of broblasts, could
introduce new tools for the specic manipulation of this
cell population, such as the Foxd1 mice [52].
What is the source of myobroblasts in renal
Fibrosis is characterized by exaggerated ECM deposition
and a striking accumulation of myobroblasts (Figure 1).
The role and origin of myobroblasts are therefore of
great interest. This is also one of the most controversially
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discussed problems in the nephrological research eld, as
obvious from a plethora of critical reviews on this matter
(for example, see [5358]). We believe in the validity of
Occams razor, i.e. that the simplest explanation making
the fewest new assumptions is the most plausible one. In
our opinion, the simplest explanation is that renal bro-
blasts are the main, if not the only, source of myobro-
blasts in renal brosis. This has indeed been recently
shown in renal brosis in mice [31]. By renal broblasts,
we mean the broad term encompassing renal interstitial
mesenchymal cells (see above). It is likely that in the
future renal broblastswill comprise several distinct cell
groups, perhaps with different names, such as cells with
pericyte-like functions, perivascular broblasts (or even
mesenchymal stem cells), cells with neuronal-like func-
tions, EPO-producing cells and vitamin A-storing cells.
We also believe that if there is any epithelial or endo-
thelial source of myobroblasts in renal brosis, this will
not be a major one. Studies analyzing the epithelial- and
endothelial-to-mesenchymal transition using genetic cell
fate tracking are summarized in Table 2and were re-
viewed in detail elsewhere [5358]. Most recent studies
from various groups that specically addressed this issue
using different methodologies did not nd any indication
of an epithelial or endothelial source of myobroblasts
[23,31,52,5962]. This does not mean that phenotypic
alteration of endothelial or tubular epithelial cells does
not contribute to brosis. Phenotypic alteration in the
course of epithelial (or endothelial )-to-mesenchymal
transition or cell-cycle arrest might lead to changes in
their paracrine cell signalling which drives broblast pro-
liferation and ECM production and induces a myobro-
blast phenotype. The role of circulating brocytes as a
contributor to renal broblast and myobroblast formation
remains controversial as well (Table 3). We have
previously reviewed these issues in more detail [2].
Some recent studies suggested that the major source of
myobroblasts in renal brosis is pericytes [23,52,55,
63]. By using marker expression such as PDGFR-β, it has
been suggested that, in the peritubular interstitium, the
mesenchymal cells are pericytes and not broblasts [23,
52,55,63]. There is currently no single marker that
would be able to discriminate a pericyte from other me-
senchymal cells [22] (Table 1). Other groups using ultra-
structural analysis did not describe pericytes in the renal
interstitium [9]. The simple denition of a pericyte is a
cell of the connective tissue about capillaries or other
small blood vessels (
medical/pericyte). Especially in the healthy renal intersti-
tium, such a denition could easily categorize most cells
Fig. 2. The origin of the renal stroma (interstitium). The nephrogenesis of metanephros is initiated when the metanephric mesenchyme (or
metanephric blastema) induces the outpouching of the ureteric bud from the Wollan duct (A). The outgrowing ureteric bud induces condensation of
some of the metanephric mesenchyme, forming condensed mesenchyme or cap cells (B). These cells are Pax-2 positive and represent the nephron
progenitor cell population. Surrounding the cap cells are a more loose and morphologically distinct cell population of mesenchymal Foxd1-positive
cells. These cells are the progenitor population for the renal stroma. These cells might originate from metanephric mesenchyme but possibly also
from the neural crest (grey arrows). At later stages, with branching of the ureteric bud (C) the condensed mesenchyme undergoes mesenchymal-to-
epithelial induction to form renal vesicles from which glomeruli and tubules develop. At this stage, the Foxd1 cells migrate along the developing
nephron and form the primary interstitium. The primary interstitium then differentiates to the mature medullary and cortical interstitium. Whether
stromal cells arise directly from the metanephric mesenchyme, uninduced intermediate mesenchyme, neural crest or combination thereof is not clear.
Representative PAS-stained section of human embryonic kidney at 20 weeks of gestation is shown in D (original magnication ×200). The
schematics (AC) were adopted from [42,43].
3032 Nephrol Dial Transplant (2012): Editorial Review
by guest on July 31, 2012 from
as pericytes. However, the true identication of pericytes
is currently possible only using ultrastructural analyses
[22], in which a mature pericyte is a cell completely or
partially embedded within the vascular basement mem-
brane [22,64]. Pericytes have processes that form contacts
with endothelial cells. These are of different types, e.g.
peg and socket, adhesion plaques and gap junctions
[22,64]. As described earlier, renal broblasts have been
described to form connections with endothelial basement
membrane and endothelial cells. To date, it is unknown
how many of the renal interstitial cellsor renal bro-
blastsmight indeed be mature pericytes. Detailed ultra-
structural and immunogold studies that assess marker
panels to characterize and quantify various phenotypes of
renal mesenchymal cells are eagerly awaited and might
solve this question [65].
According to the ultrastructural denition, mature myo-
broblasts are tissue-contracting cells. They have impor-
tant functions in wound closure but also in the initiation
of revascularization and regeneration [66]. In organs such
as the kidney, such functions are not entirely clear. It is
possible, but not proven, that myobroblasts normalize
biomechanical forces in injured organs thereby supporting
normal function in the uninjured areas and reducing
further organ damage. It has been shown that biomechani-
cal forces are crucial for correct cell differentiation and a
major trigger to induce a myobroblast phenotype [19].
In experimental renal brosis, alteration of renal intratubu-
lar hydrodynamic forces leads to phenotypic alterations of
tubular cells towards a more probrotic phenotype [67,
68]. Histology of human or experimental renal brosis
shows tubular atrophy, dilatation and loss (Figure 1). It is
well known that advanced brosis is characterized by
shrinkage of the kidneys. These data suggest that in renal
Table 2. Overview of studies using genetic cell fate tracking to analyze epithelial and endothelial source of renal (myo-)broblasts
Genetic approach Determination of transition
(colocalization with)
Animal model Study
Tracing tubular cells β-galactosidase/anti-β-galactosidase
IHC with
UUO, bone marrow chimeras [80]
(β-glutamyl-transferase-driven Cre/
Fifteen per cent of broblasts in UUO are bone
marrow derived
Thirty-six per cent of broblasts in UUO are derived
from tubular cells EMT)
Tracing tubular cells
(Pax8rtTA/LC1/ROSA26LacZ or Z/Red)
β-galactosidase/X-Gal with
Collagen 1 IHC
Overexpression of active TGF-βin tubular cells
No indication of tubular source of broblasts/EMT
Tracing tubular cells EYFP with UUO [62]
(Ksp-Cre/ROSA26-EYFP) FSP-1, α-SMA, entactin IHC No indication of tubular source of broblasts/EMT
Tracing tubular cells UUO, unilateral I/R [52]
(Six2-GFP-Cre/ROSA26LacZ or Z/Red) β-galactosidase/X-Gal, RFP with No indication of tubular source of broblasts/EMT in
any of the approaches(Hoxb7-Cre/ROSA26LacZ or Z/Red) FSP-1, α-SMA IHC
Tracing interstitial mesenchymal cells β-galactosidase/X-Gal, GFP with
(FoxD1-GFP-Cre-ER/ROSA26LacZ or Z/Red) PDGFR-β, CD73, α-SMA IHC Foxd1-traced interstitial cells form the majority of
Tracing interstitial mesenchymal cells ECFP with UUO, folic acid nephropathy, I/R [31]
(P0-Cre/ROSA26ECFP or ROSA26-tdRFP) PDGFR-β, CD73, α-SMA IHC No indication of tubular source of broblasts/EMT
P0-traced interstitial cells form the majority of
Tracing endothelial cells EYFP with UUO [82]
(Tie2-Cre/ROSA26-stop-EYFP) FSP-1, α-SMA IHC Some FSP-1 and fewer α-SMA-positive cells derived
from Tie2 traced cells
Tracing endothelial cells EGFP with STZ-induced diabetic nephropathy [83]
(Tie2-Cre/EGFP) α-SMA IHC Tie2-traced cells comprised 10% (at 1 month) and
24% (at 6 months of diabetic nephropathy) of
α-SMA, α-smooth muscle actin; EMT, epithelial-to-mesenchymal transition; FSP-1, broblast specic protein 1 (S100A4); HSP-47, heat shock protein
47; IHC, immunohistochemistry; I/R, ischemia/reperfusion injury model; STZ, streptozotocin; UUO, unilateral ureteral obstruction.
Table 3. Summary of the main conclusions of this review
Renal broblast is not a simple mesenchymal spindle-shaped cell, but
rather a term including heterogeneous population of renal interstitial
mesenchymal cells with various functions, e.g. EPO production.
The nomenclature of mesenchymal cells in general is not clearly dened,
mostly because an ultrastructural analysis is currently the only means of
identification and differentiation between various mesenchymal cells and
their transitional phenotypes.
We lack specic molecular markers that could specically differentiate
renal mesenchymal cells and their different phenotypic subgroups.
The embryonic source of renal broblasts is yet unclear, some studies
suggesting a neural crest origin.
Renal broblasts are the major, if not the only, source of renal
myobroblasts in renal brosis.
Most studies refer to the appearance of the so-called renal myobroblasts
found in renal brosis, which in most studies is described solely by α-
SMA expression, as differentiatedor transformedcells. However, it is
likely that these cells rather represent a stressedor dedifferentiated
mesenchymal cells that have lost some of their (differentiated) functions,
e.g. EPO production.
Nephrol Dial Transplant (2012): Editorial Review 3033
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brosis signicant alterations of biomechanical forces
take place, which might be a major signal for myobro-
blast formation. This is supported by the observation that
in reversible acute kidney injury myobroblasts form only
transiently during the period of tubular injury and dilata-
tion [69]. Another major signal for the induction of a
myobroblast phenotype is paracrine signalling, including
the probrotic molecules like TGF-β
[70]. Other signals
that may drive the myobroblast induction in renal bro-
sis are as yet unclear. The majority of interventions shown
to be antibrotic were also associated with a reduction of
the number of α-SMA-expressing cells [3,36,7073].
The molecules governing the phenotypic switch of bro-
blasts are not yet well dened. In vitro, a wide variety of
molecules were found to be involved in proliferation of
(myo-)broblasts. These include TGF-β, PDGF, FGF-2,
connective tissue growth factor (CTGF), tissue plasmino-
gen activator (tPA), brinogen, potassium channel
KCa3.1, high glucose or the anti-mitogenic EP
and were
reviewed previously in more detail [24,70,71,7476].
Some of the molecules involved in renal broblasts pro-
liferation might also be involved in their phenotypic
switch, and these processes might even be closely linked.
One could argue that, from a clinical point of view, the
source and precise phenotype of the expanded pool of in-
terstitial mesenchymal cells in renal brosis is irrelevant
as long as our intervention counteracts this process.
However, we believe that a better characterization und un-
derstanding of cell biology of the various renal broblast
subtypes might lead to more specic treatments or even
targeting approaches for certain subtypes of these cells.
What does the myobroblast phenotype
in brotic kidneys represent?
Most of the studies of renal brosis describe the change
of a renal broblast into a myobroblast phenotype as
activation. We hypothesize that most of the so-called
myobroblasts actually represent stressed cells that have
lost their mature, differentiated phenotype. These cells
lose their functions, alter their phenotype and proliferate,
thereby resembling a non-mature state, i.e. they dediffer-
entiate to some degree. Such changes are well described
in other mesenchymal cell types, e.g. the VSMCs but also
in pericytes [7779]. During injury, VSMCs lose the
expression of proteins characteristic of their contractile
function, thereby losing the ability to contract. Stress- or
injury-induced alterations of cell phenotype that resem-
bles the embryonic precursor were also proposed for renal
tubular cells. Tubular cells develop embryonically via me-
senchymal-to-epithelial transition from metanephric me-
senchyme (Figure 2). In renal brosis re-expression of
some mesenchymal markers in tubular cells has been ob-
served and termed epithelial-to-mesenchymal transition
(Figure 1)[2].
The same process most likely occurs in renal bro-
blasts. In renal brosis, these cells lose their ability to
produce EPO [31]. Using detailed ultrastructural analyses
from nine patients with renal brosis, only one case pre-
sented with cells with features of mature myobroblasts.
The other patients showed many different phenotypes of
myobroblast-like cells [65]. Importantly, no typical
mature broblasts were found in these biopsies either
[65]. During embryonic development, the typical markers
of myobroblasts, including αSMA, vimentin or bro-
nectin ectodomains, are expressed, but at later stages, they
are down-regulated or lost as the cells differentiate
[9,19]. Furthermore, myobroblasts, and especially their
precursor forms, have also been characterized as rather
poor construction workers[19].
Thus, at least part of what we term renal myobro-
blasts, i.e. α-SMA-expressing interstitial cells, might be
dedifferentiated renal broblasts. Vice versa,only a frac-
tion of so-called myobroblast indeed meets the criteria
of mature myobroblasts. At rst glance, this difference
might be purely semantic. We think that by acknowledging
this fact, we might move the research towards approaches
that might translate into novel therapeutic options for renal
brosis. For example, treatment that would re-establish
mature broblast phenotype could also lead to re-expression
of EPO, as was achieved in vitro [31].
What do we conclude and where do we go from
The simple, inconspicuous light-microscopic appearance
of broblasts together with a lack of specic markers is
most likely responsible for the current uncertainties in the
nomenclature of renal broblasts, or more generally, of
renal interstitial mesenchymal cells. We are beginning to
understand that the term broblast, as currently used in
the literature, comprises a large and functionally impor-
tant population of differentiated and diverse mesenchymal
Identication of specic markers for broblasts, which
will allow their specic isolation and in vitro and in vivo
characterization, are one of the essential goals for future
research. Only a combination of anatomical localization,
shape and protein expression together with ultrastructural
analyses can distinguish between various mesenchymal
cell types and their various phenotypes. Specic markers
could also facilitate genetic animal studies allowing the
specic targeting of these cells. The obvious question is
whether there are such markers at all. Characterization of
the embryonic origin and the molecules that drive their
development are other issues deserving further studies.
The world of renal broblasts is open to be conquered.
Acknowledgements. We apologize to all authors whose important work
we could not cite because of space restrictions. We thank our colleagues
for helpful discussions and for critically reviewing the manuscript. This
study was supported by a nancial research grant from the Deutsche For-
schungsgemeinschaft to P.B. (BO 3755/1-1) and J.F. (SFB TRR57, P17
and P19).
Conict of interest statement. None declared.
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Received for publication: 22.2.2012; Accepted in revised form:
3036 Nephrol Dial Transplant (2012): Editorial Review
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... Additionally, immune cells such as macrophages, T cells, and B cells are recruited and activated to synthesize several profibrotic cytokines and growth factors which in turn activate myofibroblasts and promote the deposition of extracellular matrix [109]. This fibrotic microenvironment triggers renal resident cells, such as fibroblasts, pericytes, tubular epithelial cells, endothelial cells, and bone marrow-derived cells, such as macrophages and mesenchymal stem cells, to transdifferentiate into myofibroblasts [110]. Finally, myofibroblast activation and proliferation result in the generation of a large amount of extracellular matrix. ...
Introduction: Altered lipid distribution and metabolism may lead to the development and/or progression of chronic kidney disease (CKD). Dyslipidemia is a major risk factor for CKD and increases the risk of cardiovascular events and mortality. Therefore, lipid-lowering treatments may decrease cardiovascular risk and prevent death. Areas covered: Key players involved in regulating lipid accumulation in the kidney; contribution of lipids to CKD progression, lipotoxicity, and mitochondrial dysfunction in kidney disease; recent therapeutic approaches for dyslipidemia. Expert opinion: The precise mechanisms for regulating lipid metabolism, particularly in kidney disease, are poorly understood. Guidelines for lipid-lowering therapy for CKD are controversial. Several hypolipemic therapies are available, but compared to others, statin therapy is the most common. No clinical trial has evaluated the efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in preventing cardiovascular events or improving kidney function among patients with CKD or kidney transplant recipients. Attractive alternatives, such as PCSK9-small interfering RNA (siRNA) molecules or evinacumab are available. Additionally, several promising agents, such as cyclodextrins and the FXR/TGR5 dual agonist, INT-767, can improve renal lipid metabolism disorders and delay CKD progression. Drugs targeting mitochondrial dysfunction could be an option for the treatment of dyslipidemia and lipotoxicity, particularly in renal diseases.
... Increased α-SMA expression in Zeb2 cKO mice was further confirmed by Western blot analysis(Figure 4, B and F). By analyzing vimentin, another established myofibroblast marker(44), we confirmed that α-SMA + vimentin + myofibroblasts were significantly increased in Zeb2 cKO mouse kidneys compared to wild type controls(Figure 4, C and G). Increased vimentin expression in Zeb2 cKO mice was further confirmed by Western blot analysis(Figure 4, D and H). ...
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FOXD1+ derived stromal cells give rise to pericytes and fibroblasts that support the kidney vasculature and interstitium but are also major precursors of myofibroblasts. ZEB2 is a SMAD-interacting transcription factor that is expressed in developing kidney stromal progenitors. Here we show that Zeb2 is essential for normal FOXD1+ stromal progenitor development. Specific deletion of mouse Zeb2 in FOXD1+ stromal progenitors (Zeb2 cKO) leads to abnormal interstitial stromal cell development, differentiation, and kidney fibrosis. Immunofluorescent staining analyses revealed abnormal expression of interstitial stromal cell markers MEIS1/2/3, CDKN1C, and CSPG4 (NG2) in newborn and 3-week-old Zeb2 cKO mouse kidneys. Zeb2 deficient FOXD1+ stromal progenitors also took on a myofibroblast fate that led to kidney fibrosis and kidney failure. Cell marker studies further confirmed that these myofibroblasts expressed pericyte and resident fibroblast markers including PDGFRβ, CSPG4, Desmin, GLI1, and NT5E. Notably, increased interstitial collagen deposition associated with loss of Zeb2 in FOXD1+ stromal progenitors was accompanied by increased expression of activated SMAD1/5/8, SMAD2/3, SMAD4, and AXIN2. Thus, our study identifies a key role of ZEB2 in maintaining the cell fate of FOXD1+ stromal progenitors during kidney development whereas loss of ZEB2 leads to differentiation of FOXD1+ stromal progenitors into myofibroblasts and kidney fibrosis.
... Tissue resident fibroblasts reside in the interstitium in a quiescent state and generally comprise a minor mesenchymal population in any normal tissues. Tissue fibroblasts can serve as major myofibroblast precursors in various organ fibrotic diseases, including not only liver but also lungs and kidneys [2,18,19,[106][107][108][109]. aPFs and activated lung and kidney fibroblasts share similarities with expression of common markers including Msln, Thy1, Gremlin1, Calca, Upk1b, Fbln1, CD34, Asporin, Gpc3, Bnc1, and CD200 as well as markers of perivascular mesenchymal progenitor cells such as Gli1/2, Osr1, Mfap5, and Vit [110,111]. ...
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Fibrosis is a common consequence of abnormal wound healing, which is characterized by infiltration of myofibroblasts and formation of fibrous scar. In liver fibrosis, activated Hepatic Stellate Cells (aHSCs) and activated Portal Fibroblasts (aPFs) are the major contributors to the origin of hepatic myofibroblasts. aPFs are significantly involved in the pathogenesis of cholestatic fibrosis, suggesting that aPFs may be a primary target for anti-fibrotic therapy in cholestatic injury. aPFs are distinguishable from aHSCs by specific markers including mesothelin (Msln), Mucin 16 (Muc16), and Thymus cell antigen 1 (Thy1, CD90) as well as fibulin 2, elastin, Gremlin 1, ecto-ATPase nucleoside triphosphate diphosphohydrolase 2. Msln plays a critical role in activation of PFs, via formation of Msln-Muc16-Thy1 complex that regulates TGFβ1/TGFβRI-mediated fibrogenic signaling. The opposing pro- and anti-fibrogenic effects of Msln and Thy1 are key components of the TGFβ1-induced activation pathway in aPFs. In addition, aPFs and activated lung and kidney fibroblasts share similarities across different organs with expression of common markers and activation cascade including Msln-Thy1 interaction. Here, we summarize the potential function of Msln in activation of PFs and development of cholestatic fibrosis, offering a novel perspective for anti-fibrotic therapy targeting Msln.
... Several pathways that regulate the phenotype transition were described, especially PDGF receptor (PDGFR) signaling pathway [158,168]. Resident fibroblasts in the kidney are positive for CD73 and PDGFR-β. Activation of PDGF-BB/ PDGFR-β axis is responsible for the regenerative function of the renal tubular epithelium [158,160]. ...
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This article is a review of new advances in histology, concerning either classification or structure of different tissular elements (basement membrane, hemidesmosomes, urothelium, glandular epithelia, adipose tissue, astrocytes), and various organs' constituents (blood-brain barrier, human dental cementum, tubarial salivary glands, hepatic stellate cells, pineal gland, fibroblasts of renal interstitium, Leydig testicular cells, ovarian hilar cells), as well as novel biotechnological techniques (tissue engineering in angiogenesis), recently introduced.
... 12 The fibrotic microenvironment triggers renal resident cells such as fibroblasts, pericytes, TECs, and endothelial cells, and bone marrow-derived cells like macrophages, mesenchymal stem cells transdifferentiate into myofibroblasts. 13 The activation and proliferation of myofibroblasts produce a large amount of ECM. Interstitial ECM expansion accelerates hypoxia and nephron loss. ...
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Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that is characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity and oxidative stress are the driving force for the loss of nephron including tubules, glomerulus, and endothelium. NLRP3 inflammasome signaling, MAPK signaling, PI3K/Akt signaling, and RAAS signaling involves in lipotoxicity. The upregulated Nox expression and the decreased Nrf2 expression result in oxidative stress directly. The injured renal resident cells release proinflammatory cytokines and chemokines to recruit immune cells such as macrophages from bone marrow. NF-κB signaling, NLRP3 inflammasome signaling, JAK-STAT signaling, Toll-like receptor signaling, and cGAS-STING signaling are major signaling pathways that mediate inflammation in inflammatory cells including immune cells and injured renal resident cells. The inflammatory cells produce and secret a great number of profibrotic cytokines such as TGF-β1, Wnt ligands, and angiotensin II. TGF-β signaling, Wnt signaling, RAAS signaling, and Notch signaling evoke the activation of myofibroblasts and promote the generation of ECM. The potential therapies targeted to these signaling pathways are also introduced here. In this review, we update the key signaling pathways of lipotoxicity, oxidative stress, inflammation, and myofibroblasts activation in kidneys with chronic injury, and the targeted drugs based on the latest studies. Unifying these pathways and the targeted therapies will be instrumental to advance further basic and clinical investigation in CKD.
... Chronic kidney disease (CKD) occurs when the structure and function of the kidneys become impaired and are unable to return to normal over several months or years. The occurrence of CKD is mainly due to chronic kidney damage, and loss of function as normal tissue is replaced by interstitial fibrotic tissue [1]. Fibrotic tissue damages normal tissue, preventing its regeneration and function. ...
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Diabetic nephropathy (DN) is one of the most severe chronic kidney diseases in diabetes and is the main cause of end-stage renal disease (ESRD). Protocatechuic aldehyde (PCA) is a natural product with a variety of effects on pulmonary fibrosis. In this study, we examined the effects of PCA in C57BL/KS db/db male mice. Kidney morphology, renal function indicators, and Western blot, immunohistochemistry, and hematoxylin and eosin (H&E) staining data were analyzed. The results revealed that treatment with PCA could reduce diabetic-induced renal dysfunction, as indicated by the urine albumin-to-creatinine ratio (db/m: 120.1 ± 46.1μg/mg, db/db: 453.8 ± 78.7 µg/mg, db/db + 30 mg/kg PCA: 196.6 ± 52.9 µg/mg, db/db + 60 mg/kg PCA: 163.3 ± 24.6 μg/mg, p < 0.001). However, PCA did not decrease body weight, fasting plasma glucose, or food and water intake in db/db mice. H&E staining data revealed that PCA reduced glomerular size in db/db mice (db/m: 3506.3 ± 789.3 μm2, db/db: 6538.5 ± 1818.6 μm2, db/db + 30 mg/kg PCA: 4916.9 ± 1149.6 μm2, db/db + 60 mg/kg PCA: 4160.4 ± 1186.5 μm2p < 0.001). Western blot and immunohistochemistry staining indicated that PCA restored the normal levels of diabetes-induced fibrosis markers, such as transforming growth factor-beta (TGF-β) and type IV collagen. Similar results were observed for epithelial-mesenchymal transition-related markers, including fibronectin, E-cadherin, and α-smooth muscle actin (α-SMA). PCA also decreased oxidative stress and inflammation in the kidney of db/db mice. This research provides a foundation for using PCA as an alternative therapy for DN in the future.
... A marker of myofibroblasts and therefore a state of fibrosis, ACTA2 demonstrated the anticipated increase in expression with TGF-β, TNF-α had no effect. [6,270,271] Likewise, FN1 and LAMB2 expression followed the expected increase in expression with TGF-β. [272][273][274] Interestingly, co-treatment resulted in LAMB2 expression to be statistically increased, suggesting synergy between TGF-β and TNF-α, genetic mutations in LAMB2 have been identified as causing glomerular disease. ...
Glomerulosclerosis is a feature of many chronic kidney diseases. Glomeruli are composed of glomerular endothelial cells (GECs), podocytes (PODs) and mesangial cells (MCs), and dysregulation in the interaction between these cell types results in glomerulosclerosis. This is characterised by excessive extracellular matrix deposition and cell dysfunction leading to disproportionate MC proliferation and POD loss. Animal models of glomerulosclerosis often do not reflect disease pathophysiology and 2D glomerular cell monocultures provide limited insight into a disease in which cellular crosstalk and interaction are fundamental. This thesis describes a 3D tri‐culture model in which GECs, PODs and MCs are co-cultured in a collagen matrix and used to model human glomerulosclerosis with the treatment of TGF‐β. Fibrosis is replicated in the 3D tri‐culture model with nodule formation and upregulated fibrotic/inflammatory‐associated gene expression. Whilst many cytokines were identified as playing a role in the development of fibrosis in the 3D tri‐culture, TGF‐β and CTGF were demonstrated as key inducers of fibrosis. With a synergistic relationship, both cytokines required targeting for successful attenuation of fibrosis. Direct targeting of TGF‐β is impractical due to its varied and systemic modes of action. Integrin αvβ8 activates LTGF‐β to TGF‐β, and inhibition of αvβ8 proved to reduce TGF‐β evoked fibrosis in the 3D tri‐culture model. This thesis concludes that the intimate interaction of glomerular cells both physically and via signalling mechanisms in the 3D tri‐culture model mimic the in vivo state both morphologically and pathophysiologically. This is required for successful study, identification and assessment of potential therapeutic targets of glomerulosclerosis.
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The smoothened (Smo) receptor facilitates hedgehog signaling between kidney fibroblasts and tubules during acute kidney injury (AKI). Tubule-derived hedgehog is protective in AKI, but the role of fibroblast-derived Smo is unclear. Here, we report that Smo ablation in fibroblasts mitigated tubular cell apoptosis and inflammation, enhanced perivascular mesenchymal activities, and preserved kidney function after AKI. Global proteomics of these kidneys identified extracellular matrix proteins, and nidogen-1 glycoprotein in particular, as key response markers; Intriguingly, Smo was bound to nidogen-1 in cells, suggesting that loss of Smo could impact nidogen-1 accessibility. Phosphoproteomics revealed that the ‘AKI protector’ Wnt pathway was activated in these kidneys, and in vitro and ex vivo , nidogen-1 was able to induce Wnts and repress tubular cell apoptosis. Altogether, our results support that fibroblast-derived Smo dictates AKI fate through cell-matrix interactions, including nidogen-1, and establish a robust resource and path to further dissect AKI pathogenesis.
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Intermediate filaments belong to a large family of proteins which contribute to the formation of the cytoskeleton. The immunolocalization of cytoskeletal proteins has been used extensively in the diagnosis of various renal pathologies. The present study described the immunolocalization of the cytoskeletal proteins vimentin, desmin, smooth muscle actin, and cytokeratin 19 in the normal kidney of the dromedary camel. Kidney samples from eight adult camels were processed for histology and immunohistochemistry. The kidney was enclosed in a renal capsule composed of vimentin immunoreactive fibroblasts and smooth muscle actin immunoreactive smooth muscle cells. The smooth muscle cells in the renal capsule did not exhibit desmin immunoreactivity. Podocytes forming the visceral layer of the glomerular capsule were immunoreactive for vimentin. Immunoreactivity for vimentin and smooth muscle actin in the parietal layer of the glomerular capsule varied, with both reactive and non-reactive cells observed. Intraglomerular mesangial cells were immunoreactive for smooth muscle actin and desmin, but non-reactive to vimentin. The endothelial lining of blood vessels was vimentin immunoreactive, while smooth muscle actin and desmin were demonstrated in the smooth muscle cells of the vessels. The thin limbs of the loops of Henle in cortical nephrons displayed vimentin immunoreactivity. The proximal and distal convoluted tubules, as well as the collecting ducts were negative to vimentin, smooth muscle actin, desmin and cytokeratin 19 immunostaining. In conclusion, the present study has revealed that similarities and differences exist in the immunolocalization of cytoskeletal proteins in the camel when compared to other mammals. The presence of smooth muscle actin in the parietal cells of the glomerular capsule suggests a contractile function of these cells. The results of the study indicate that vimentin and smooth muscle actin can be used as markers for the identification of podocytes and intraglomerular mesangial cells, respectively, in the camel kidney.
Chronic kidney disease (CKD) is characterized by pathological accumulation of extracellular matrix (ECM) proteins in renal structures. Tubulointerstitial fibrosis is observed in glomerular diseases as well as in the regeneration failure of acute kidney injury (AKI). Therefore, finding antifibrotic therapies comprises an intensive research field in Nephrology. Nowadays, ECM is not only considered as a cellular scaffold, but also exerts important cellular functions. In this review, we describe the cellular and molecular mechanisms involved in kidney fibrosis, paying particular attention to ECM components, profibrotic factors and cell–matrix interactions. In response to kidney damage, activation of glomerular and/or tubular cells may induce aberrant phenotypes characterized by overproduction of proinflammatory and profibrotic factors, and thus contribute to CKD progression. Among ECM components, matricellular proteins can regulate cell–ECM interactions, as well as cellular phenotype changes. Regarding kidney fibrosis, one of the most studied matricellular proteins is cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), currently considered as a fibrotic marker and a potential therapeutic target. Integrins connect the ECM proteins to the actin cytoskeleton and several downstream signaling pathways that enable cells to respond to external stimuli in a coordinated manner and maintain optimal tissue stiffness. In kidney fibrosis, there is an increase in ECM deposition, lower ECM degradation and ECM proteins cross-linking, leading to an alteration in the tissue mechanical properties and their responses to injurious stimuli. A better understanding of these complex cellular and molecular events could help us to improve the antifibrotic therapies for CKD.
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Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E(2) (PGE(2)) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral obstruction leads to progressive tubulointerstitial fibrosis with macrophage infiltration and myofibroblast proliferation. This was accompanied by an upregulation of COX-2 and PGE(2) receptor subtype EP(4) mRNAs. In the kidneys of EP(4) gene knockout mice, however, obstruction-induced histological alterations were significantly augmented. In contrast, an EP(4)-specific agonist significantly attenuated these alterations in the kidneys of wild-type mice. The mRNAs for macrophage chemokines and profibrotic growth factors were upregulated in the kidneys of wild-type mice after ureteral obstruction. This was significantly augmented in the kidneys of EP(4)-knockout mice and suppressed by the EP(4) agonist but only in the kidneys of wild-type mice. Notably, COX-2 and MCP-1 proteins, as well as EP(4) mRNA, were localized in renal tubular epithelial cells after ureteral obstruction. In cultured renal fibroblasts, another EP(4)-specific agonist significantly inhibited PDGF-induced proliferation and profibrotic connective tissue growth factor production. Hence, an endogenous PGE(2)-EP(4) system in the tubular epithelium limits the development of tubulointerstitial fibrosis by suppressing inflammatory responses.
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The kidney is a highly vascularized organ that normally receives a fifth of the cardiac output. The unique spatial arrangement of the kidney vasculature with each nephron is crucial for the regulation of renal blood flow, GFR, urine concentration, and other specialized kidney functions. Thus, the proper and timely assembly of kidney vessels with their respective nephrons is a crucial morphogenetic event leading to the formation of a functioning kidney necessary for independent extrauterine life. Mechanisms that govern the development of the kidney vasculature are poorly understood. In this review, we discuss the anatomical development, embryological origin, lineage relationships, and key regulators of the kidney arterioles and postglomerular circulation. Because renal disease is associated with deterioration of the kidney microvasculature and/or the reenactment of embryonic pathways, understanding the morphogenetic events and processes that maintain the renal vasculature may open new avenues for the preservation of renal structure and function and prevent the progression of renal disease.
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Fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) are nonhematopoietic stromal cells of lymphoid organs. They influence the migration and homeostasis of naive T cells; however, their influence on activated T cells remains undescribed. Here we report that FRCs and LECs inhibited T cell proliferation through a tightly regulated mechanism dependent on nitric oxide synthase 2 (NOS2). Expression of NOS2 and production of nitric oxide paralleled the activation of T cells and required a tripartite synergism of interferon-γ, tumor necrosis factor and direct contact with activated T cells. Notably, in vivo expression of NOS2 by FRCs and LECs regulated the size of the activated T cell pool. Our study elucidates an as-yet-unrecognized role for the lymph node stromal niche in controlling T cell responses.
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In chronic kidney disease, fibroblast dysfunction causes renal fibrosis and renal anemia. Renal fibrosis is mediated by the accumulation of myofibroblasts, whereas renal anemia is mediated by the reduced production of fibroblast-derived erythropoietin, a hormone that stimulates erythropoiesis. Despite their importance in chronic kidney disease, the origin and regulatory mechanism of fibroblasts remain unclear. Here, we have demonstrated that the majority of erythropoietin-producing fibroblasts in the healthy kidney originate from myelin protein zero-Cre (P0-Cre) lineage-labeled extrarenal cells, which enter the embryonic kidney at E13.5. In the diseased kidney, P0-Cre lineage-labeled fibroblasts, but not fibroblasts derived from injured tubular epithelial cells through epithelial-mesenchymal transition, transdifferentiated into myofibroblasts and predominantly contributed to fibrosis, with concomitant loss of erythropoietin production. We further demonstrated that attenuated erythropoietin production in transdifferentiated myofibroblasts was restored by the administration of neuroprotective agents, such as dexamethasone and neurotrophins. Moreover, the in vivo administration of tamoxifen, a selective estrogen receptor modulator, restored attenuated erythropoietin production as well as fibrosis in a mouse model of kidney fibrosis. These findings reveal the pathophysiological roles of P0-Cre lineage-labeled fibroblasts in the kidney and clarify the link between renal fibrosis and renal anemia.
Comprehensive Clinical Nephrology provides you with all the tools you need to manage all forms of kidney disease. Drs. Jürgen Floege, Richard J. Johnson, John Feehally and a team of international experts have updated this fourth edition to include hot topics such as treatment of hypertensive emergencies, herbal and over-the-counter medicines and the kidney, neurologic complications of the kidney, and more. In print and online at, this essential resource gives you quick access to today's best knowledge on every clinical condition in nephrology. Make efficient, informed decisions with just the right amount of basic science and practical clinical guidance for every disorder.Diagnose effectively and treat confidently thanks to more than 1100 illustrations, abundant algorithms, and tables that highlight key topics and detail pathogenesis for a full range of kidney conditions and clinical management.Access the fully searchable text online at, along with a downloadable image gallery.Get coverage of the latest developments in the field with 18 new chapters on the Management of the Diabetic Patient with Chronic Kidney Disease, Treatment of Hypertensive Emergencies, Principles of Drug Dosing and Prescribing of Chronic Kidney Disease, Herbal and Over-the-Counter Medicines and the Kidney, Neurologic Complications of the Kidney, and more.Tap into the experience and expertise of the world's leading authorities in the field of nephrology.Floege, Johnson, and Feehally give you the information you need to make quick and correct clinical decisions.
Fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) are non-hematopoietic stromal cells of lymphoid organs. They influence the migration and homeostasis of naïve T cells; however, their influence on activated T cells remains undescribed. We have recently identified that FRCs and LECs inhibited T cell proliferation through regulated nitric oxide synthase-2(NOS2)-dependent mechanism. Importantly, in vivo NOS2 expression by FRCs and LECs controlled the size of the activated T cell pool. Mechanistically, the expression of NOS2 and production of nitric oxide (NO) paralleled the activation of T cells and required IFNGR1 signaling in FRCs and LECs, and was augmented by TNF and direct contact with activated T cells. Comparative transcriptomic analysis revealed that various adhesion molecules and multiple components of cytokine, complement and JAK-STAT signaling pathways are upregulated in FRCs in the presence of activated T cells. Based on these data, current efforts aim to identify the molecules involved in the direct stromal cell-T cell interaction influencing NO production by FRCs. This negative regulatory feedback mechanism is likely of great relevance to regulation of immune responses either to prevent excessive T cell expansion or to avoid structural damage within LNs caused by the expanding T cell pool.
Pericytes, the mural cells of blood microvessels, have recently come into focus as regulators of vascular morphogenesis and function during development, cardiovascular homeostasis, and disease. Pericytes are implicated in the development of diabetic retinopathy and tissue fibrosis, and they are potential stromal targets for cancer therapy. Some pericytes are probably mesenchymal stem or progenitor cells, which give rise to adipocytes, cartilage, bone, and muscle. However, there is still confusion about the identity, ontogeny, and progeny of pericytes. Here, we review the history of these investigations, indicate emerging concepts, and point out problems and promise in the field of pericyte biology.