Expanding targets of vitamin D receptor activation: Downregulation of several RAS components in the kidney
Vitamin D receptor (VDR) activation has a beneficial influence on the progression of experimental renal insufficiency, and reduced renal tissue renin expression may play a role in this process. Freundlich and co-workers now report that VDR activation also suppresses the expression of angiotensinogen, angiotensin II type 1 receptor, and renin receptor in the kidneys of 5/6 nephrectomized rats, effects associated with reduced blood pressure and urinary protein excretion and with alleviated renal tissue damage.
Kidney International (2008) 74 1371
© 2008 International Society of Nephrology
see original article on page 1394
Expanding targets of
vitamin D receptor activation:
downregulation of several RAS
components in the kidney
Ilkka H. Pörsti
Vitamin D receptor (VDR) activation has a beneficial influence on the
progression of experimental renal insufficiency, and reduced renal
tissue renin expression may play a role in this process. Freundlich
and co-workers now report that VDR activation also suppresses the
expression of angiotensinogen, angiotensin II type 1 receptor, and renin
receptor in the kidneys of 5/6 nephrectomized rats, effects associated
with reduced blood pressure and urinary protein excretion and with
alleviated renal tissue damage.
Kidney International (2008) 74, 1371–1373. doi:10.1038/ki.2008.424
Vitamin D: regulation of plasma calcium
and phosphate, and a lot more
Vitamin D is not only involved in the regu-
lation of calcium homeostasis and bone
mineralization via vitamin D receptor
(VDR) activation but also has antiprolif-
erative, pro-dierentiation, and immuno-
modulatory activities. e VDR is found
ubiquitously throughout the body and has
been well characterized in the parathyroid
cells, osteoblasts, and intestinal enterocytes.
However, the function of the VDR in many
other tissues has not been established. In
addition to the treatment of secondary
hyperparathyroidism, the potential value
of vitamin D and its metabolites has been
of considerable interest in many other
diseases, including osteoporosis, cancer,
autoimmune diseases, and infectious dis-
eases. e vitamin D endocrine system also
participates in the regulation of blood pres-
sure, volume homeostasis, cardiac function,
and protection of renal cellular integrity
(reviewed by Holick
It seems clear that the altered vitamin D
status contributes to the cardiovascular
pathology in chronic renal insuciency,
with associated changes in the function
of various tissues, including vascular
smooth muscle and the heart. In hemo-
dialysis patients, the treatment of second-
ary hyperparathyroidism by calcitriol
has been suggested to induce regression
of myocardial hypertrophy. A reduced
calcitriol level may also contribute to the
enhanced brogenesis in chronic renal
e nonclassical mecha-
nisms of VDR activation may play an
important role in the alleged improved
survival of patients with renal failure
treated with calcitriol or its analogues.
e local intrarenal renin–angiotensin
system (RAS) is an important determi-
nant of kidney tissue injury, inamma-
tion, and progression of renal disease, and
inhibition of the actions of the RAS can
preserve renal function in chronic kidney
An inverse relationship between
plasma calcitriol and renin activity was
observed more than two decades ago in
patients with essential hypertension.
concert with these seminal ndings, mice
lacking the VDR and mice with inhibited
calcitriol synthesis showed hypertension,
increased renal expression of renin,
elevated angiotensin II (Ang II) levels,
and cardiac hypertrophy.
Today a widely
accepted concept is that VDR activation
is a negative endocrine regulator of renin
expression in the kidney independent of
Vitamin D receptor activation
and the renal renin–angiotensin system
VDR activation regulates the expres-
sion of a large number of genes in the
e results of Freundlich and
(this issue) indicate that the
eects of VDR activation on RAS compo-
nents are not limited to reduced expres-
sion of renin. In 5/6 nephrectomized rats,
treatment with pari calcitol was associ-
ated with suppression of several RAS
components in the kidney: renin, renin
receptor, angiotensinogen, and Ang II
type 1 receptor (AT
treatment also reduced blood pressure,
proteinuria, glomerular sclerosis, and
tubulointerstitial damage, thus retarding
the progression of renal tissue damage,
with associated reduced expression of
vascular endothelial growth factor and
transforming growth factor-β (TGF-β).
Decreased TGF-β expression following
VDR activation appears to be an impor-
tant mechanism to reduce brogenesis
in the kidney. It is of note that calcitriol
can inhibit matrix-producing interstitial
myobroblast activation via upregulation
of antibrotic hepatocyte growth factor
gene expression, and that VDR activation
may exert renoprotective activity by sup-
pressing inammatory-cell inltration
and inhibiting nuclear factor-κB activa-
tion. e lack of VDR activation may thus
also result in increased susceptibility to
The findings of Freundlich and co-
are supported by recent obser-
vations in mice made decient in calcitriol
by targeted ablation of the 1α-(OH)
ase gene, which showed that exogenous
calcitriol not only normalized serum
calcium and phosphorus levels but also
normalized blood pressure, cardiac
structure–function, and RAS components,
as evaluated by measurements of plasma
renin activity, plasma Ang II, and aldos-
terone concentrations, as well as renin and
Medical School, University of Tampere, and
Department of Internal Medicine, Tampere
University Hospital, Tampere, Finland
Correspondence: Ilkka Pörsti, Medical School/
Internal Medicine, FIN-33014 , University of
Tampere, Tampere, Finland.
1372 Kidney International (2008) 7 4
higher, and the same holds true for the
number of RAS regulators. VDR activa-
tion has established or newly suggested
eects on renin, angiotensinogen, Ang II,
R, and renin receptor, but the inu-
ences remain unknown on Ang II type 2
and type 4 receptors (AT
R and AT
angiotensin-converting enzyme 2, and the
receptor mas oncogene,
which contribute to cardiovascular func-
tion and growth.
Via reduction of renin
and angiotensinogen, VDR activation also
has the potential to inuence the levels of
and the novel angiotensin
, formed from
angiotensinogen via non-renin mecha-
nisms. VDR can cross-talk with diverse
cellular signals by forming complexes with
a wide variety of transcription factors,
the inuence of VDR activation on several
RAS components remains to be elucidated
More active treatment with vitamin D
receptor activators — or combination
The synergism between VDR activa-
tion and RAS inhibition carries interest-
ing therapeutic potential. Low vitamin
D status is common not only in patients
with chronic kidney disease but also in
the general population.
e ndings on
RAS favor a more active treatment with
VDR activators in chronic kidney disease
patients. However, the use of VDR ana-
logues appears to suppress endogenous
calcitriol levels in plasma, but what hap-
pens in the long term at the tissue level is
unknown. is may be important, as cal-
citriol and activated vitamin D analogues
may dier in their ancillary eects, and
some of the ancillary eects may favor the
analogues, but others may favor calcitriol.
e 1α-(OH)ase is widely distributed, and
local calcitriol synthesis from calcidiol may
play an important role in regulation of vari-
ous cellular processes in dierent tissues.
An unanswered question is whether there
is a need to ensure normal concentrations
of calcidiol — or calcitriol — in addition to
the use of a VDR analogue.
Can we clinically inuence RAS com-
ponents in vivo in humans with VDR acti-
vators without side eects; does this have
an inuence on the progression of renal
disease; and what doses are needed? e
remains that VDR stimulation especially
affected the genes activated following
surgery. Moreover, if the study protocol
had included a longer disease progression
period following renal mass reduction,
the outcome might not have been quite as
favorable. However, inhibition of calcitriol
synthesis in normal mice increases renin
expression, whereas calcitriol injection
results in renin suppression.
of activated RAS in VDR knockout mice,
and in mice with targeted ablation of the
1α-(OH)ase gene, indicate that renal abla-
tion is not a prerequisite for VDR activa-
tion to inuence RAS components.
e cell types responsible for the dif-
ferences in RAS component expression
aer VDR activation remain unknown.
Following renal mass reduction there is
suppressed juxtaglomerular renin syn-
thesis but de novo synthesis of renin in
the tubular epithelium. In contrast to the
normal increase in juxtaglomerular renin,
tubular renin expression is reduced with
angiotensin-converting enzyme inhibi-
R expression in 5/6
nephrectomized rats is also increased
in the interstitial component in areas
of tissue injury, whereas in normal rats
the expression is predominantly tubular.
VDR activation with paricalcitol can thus
be argued to have inuenced the patho-
logical expression of RAS components
following 5/6 nephrectomy.
The renin–angiotensin system:
e RAS is becoming ever more complex
and the number of its known components
angiotensinogen mRNA levels and renin
protein levels in the kidney.
interesting report, by Zhang and co-
workers, recently showed that diabetic
VDR knockout mice develop more severe
albuminuria and glomerulosclerosis than
wild-type control mice, and that increased
expression of renin, angiotensinogen,
TGF-β, and connective tissue growth
factor accompanied more severe renal
Their results indicate that
receptor-mediated vitamin D actions are
renoprotective in experimental diabetic
nephropathy and that higher activation
of the intrarenal RAS is the key factor to
induce more severe diabetic nephropathy
in VDR knockout mice.
e inhibition of the RAS by medical
compounds is oen referred to as being
renoprotective, but despite active drug
treatment, the course of many renal dis-
eases can only be slowed down, not pre-
vented. erefore, all additional treatment
modalities are welcome, and VDR activa-
tion may be one such approach. Supporting
a synergistic action between VDR activa-
tion and pharmacological RAS blockade,
paricalcitol treatment was found to retard
the progression of experimental renal
insuciency via an eect on the TGF-β
signaling pathway, and this effect was
amplied with simultaneous angiotensin-
converting enzyme inhibition.
Some remarks on study limitations
e experiment design did not include
a sham-operated group treated with
As the treatment already
started 4 days aer surgery, the possibility
Figure 1 | Established or newly suggested effects of vitamin D receptor activation on the
components of the renin–angiotensin system.
Kidney International (2008) 74 1373
ongoing randomized clinical trials on the
eects of VDR activation on renal failure-
induced cardiac mortality and the progres-
sion of albuminuria (PRIMO and VITAL)
seem highly warranted, and we are awaiting
the results. e present results of Freund-
lich et al.
show that the expanding targets
of VDR activation include downregulation
of multiple RAS components.
The author has received consulting or lecture
fees from Abbott Finland, Bayer Schering
Pharma Finland, Boehringer Ingelheim Finland,
MSD Finland, and Novartis Finland.
Work in the laboratory was supported by
the Finnish Foundation for Cardiovascular
Research, the Paavo Nurmi Foundation, the
Pirkanmaa Regional Fund of the Finnish
Cultural Foundation, the Tampere Tuberculosis
Foundation, and the Competitive Research
Funding of the Pirkanmaa Hospital District.
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see original article on page 1403
Regulation of the Na
cotransporter by dietary NaCl:
a role for WNKs, SPAK, OSR1,
This Commentary aims to integrate or interrelate the available data with
the current study by Chiga and co-workers, which defines an important
influence of aldosterone in the phosphorylation and thus activation of
cotransporter (NCC) in response to changes in NaCl intake
and implicates the involvement of SPAK/OSR1 kinases and WNKs.
Kidney International (2008) 74, 1373–1375. doi:10.1038/ki.2008.477
An impaired ability of the kidney to
excrete NaCl plays a critical pathophysi-
ological role for a long-term increase in
blood pressure. e aldosterone-sensi-
tive distal nephron is of primary impor-
tance in the regulation of renal NaCl
excretion and thus body NaCl home-
ostasis. e stimulatory eect of aldos-
terone on the epithelial sodium channel
(ENaC) is well known and primarily
localized to the late distal convoluted
tubule (DCT) and connecting tubule.
Less appreciated is the regulation of the
cotransporter (NCC) in the
DCT by aldosterone and other regula-
tors. Moreover, whereas much has been
learned about the molecular pathways
involved in the regulation of ENaC,
still relatively little is known about the
determinants of NCC activity. e study
by Chiga and co-workers
provides new in vivo evidence in this
regard, as they indicate an important
role of aldosterone in the regulation of
NCC phosphorylation by dietary salt
intake. Moreover, evidence is provided
that the signaling cascade involves with-
no-lysine kinase (WNK) and the mam-
malian STE20 (sterile 20)-like kinases
SPAK (STE20/SPS1-related proline/
alanine-rich kinase) and OSR1 (oxida-
tive stress-responsive kinase-1).
SPAK and OSR1 were discovered
through their ability to interact with,
phosphorylate, and stimulate the activ-
ity of the Na
(NKCC1), a member of a superfamily of
electroneutral cation-coupled chloride
cotransporters (SLC12) (reviewed by
Delpire and Gagnon
). e Na
members of this superfamily include
NKCC1 and NKCC2, as well as NCC.
Fragments of these cotransporters con-
taining a cluster of conserved threonine
residues are phosphorylated in vitro by
the SPAK/OSR1 kinases. e SPAK and
OSR1 enzymes themselves are phospho-
rylated and activated by the WNK1 and
WNK4 protein kinases (reviewed by
Delpire and Gagnon
). ese ndings
suggest that a signaling cascade includ-
ing WNK1, WNK4, and SPAK/OSR1
could be involved in the regulation of
-driven members of the SLC12
superfamily, including NCC.
WNK1 and WNK4 are mutated in
patients with pseudohypoaldosteronism
Department of Medicine, University of California,
San Diego, California, USA;
Pharmacology, University of California, San Diego,
California, USA; and
VA San Diego Healthcare
System, San Diego, California, USA
Correspondence: Volker Vallon, VA San Diego
Healthcare System, 3350 La Jolla Village Drive,
San Diego, California 92161, USA.