Expanding targets of vitamin D receptor activation: Downregulation of several RAS components in the kidney

Article (PDF Available)inKidney International 74(11):1371-3 · January 2009with11 Reads
DOI: 10.1038/ki.2008.424 · Source: PubMed
Abstract
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.

Figures

Kidney International (2008) 74 1371
commentary
http://www.kidney-international.org
© 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
1
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-dierentiation, 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
1
and Andress
2
).
It seems clear that the altered vitamin D
status contributes to the cardiovascular
pathology in chronic renal insuciency,
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
insuciency.
3
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.
4
e local intrarenal renin–angiotensin
system (RAS) is an important determi-
nant of kidney tissue injury, inamma-
tion, and progression of renal disease, and
inhibition of the actions of the RAS can
preserve renal function in chronic kidney
disease.
5
An inverse relationship between
plasma calcitriol and renin activity was
observed more than two decades ago in
patients with essential hypertension.
6
In
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.
7
Today a widely
accepted concept is that VDR activation
is a negative endocrine regulator of renin
expression in the kidney independent of
calcium metabolism.
Vitamin D receptor activation
and the renal renin–angiotensin system
VDR activation regulates the expres-
sion of a large number of genes in the
kidney.
8
e results of Freundlich and
co-workers
9
(this issue) indicate that the
eects 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
1
R). Paricalcitol
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
myobroblast activation via upregulation
of antibrotic hepatocyte growth factor
gene expression, and that VDR activation
may exert renoprotective activity by sup-
pressing inammatory-cell inltration
and inhibiting nuclear factor-κB activa-
tion. e lack of VDR activation may thus
also result in increased susceptibility to
inammatory stimulation.
2,4
The findings of Freundlich and co-
workers
9
are supported by recent obser-
vations in mice made decient 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
1
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.
E-mail: ilkka.porsti@uta.fi
1372 Kidney International (2008) 7 4
commentary
higher, and the same holds true for the
number of RAS regulators. VDR activa-
tion has established or newly suggested
eects on renin, angiotensinogen, Ang II,
AT
1
R, and renin receptor, but the inu-
ences remain unknown on Ang II type 2
and type 4 receptors (AT
2
R and AT
4
R),
angiotensin-converting enzyme 2, and the
angiotensin
(1–7)
receptor mas oncogene,
which contribute to cardiovascular func-
tion and growth.
5
Via reduction of renin
and angiotensinogen, VDR activation also
has the potential to inuence the levels of
angiotensin
(1–7)
and the novel angiotensin
precursor angiotensin
(1–12)
, 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,
2
and
the inuence of VDR activation on several
RAS components remains to be elucidated
(Figure 1).
More active treatment with vitamin D
receptor activators — or combination
treatment?
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.
1
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 dier in their ancillary eects, and
some of the ancillary eects may favor the
analogues, but others may favor calcitriol.
4
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 dierent tissues.
1,2
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 inuence RAS com-
ponents in vivo in humans with VDR acti-
vators without side eects; does this have
an inuence 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.
7
e reports
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 inuence RAS components.
10,11
e cell types responsible for the dif-
ferences in RAS component expression
aer VDR activation remain unknown.
9
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-
tion.
13
Renal AT
1
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 inuenced the patho-
logical expression of RAS components
following 5/6 nephrectomy.
The renin–angiotensin system:
increasing complexity
e RAS is becoming ever more complex
and the number of its known components
angiotensinogen mRNA levels and renin
protein levels in the kidney.
10
Another
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
injury.
11
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 oen 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
insuciency via an eect on the TGF-β
signaling pathway, and this effect was
amplied with simultaneous angiotensin-
converting enzyme inhibition.
12
Some remarks on study limitations
e experiment design did not include
a sham-operated group treated with
paricalcitol.
9
As the treatment already
started 4 days aer surgery, the possibility
Figure 1 | Established or newly suggested effects of vitamin D receptor activation on the
components of the renin–angiotensin system.
Renin
Renin/prorenin
receptor
Angiotensinogen
Angiotensin II
AT
1
receptor
AT
4
receptor?
AT
2
receptor?
Angiotensin-converting
enzyme ±
Angiotensin-converting
enzyme 2?
VDR activation
mas oncogene?
Angiotensin
(1–7)
?
Angiotensin
(1–12)
?
Kidney International (2008) 74 1373
commentary
ongoing randomized clinical trials on the
eects 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.
9
show that the expanding targets
of VDR activation include downregulation
of multiple RAS components.
DISCLOSURE
The author has received consulting or lecture
fees from Abbott Finland, Bayer Schering
Pharma Finland, Boehringer Ingelheim Finland,
MSD Finland, and Novartis Finland.
ACKNOWLEDGMENTS
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.
REFERENCES
1. Holick MF. Vitamin D deficiency. N Engl J Med 2007;
357: 266–281.
2. Andress DL. Vitamin D in chronic kidney disease:
a systemic role for selective vitamin D receptor
activation. Kidney Int 2006; 69: 33–43.
3. Achinger SG, Ayus JC. The role of vitamin D in left
ventricular hypertrophy and cardiac function.
Kidney Int Suppl 2005; S37–S42.
4. Kovesdy CP, Kalantar-Zadeh K. Vitamin D receptor
activation and survival in chronic kidney disease.
Kidney Int 2008; 73: 1355–1363.
5. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM.
Renin-angiotensin system and cardiovascular risk.
Lancet 2007; 369: 1208–1219.
6. Resnick LM, Muller FB, Laragh JH. Calcium-
regulating hormones in essential hypertension.
Relation to plasma renin activity and sodium
metabolism. Ann Intern Med 1986; 105: 649–654.
7. Li YC, Kong J, Wei M et al. 1,25-Dihydroxyvitamin
D(3) is a negative endocrine regulator of the
renin-angiotensin system. J Clin Invest 2002; 110:
229–238.
8. Li X, Zheng W, Li YC. Altered gene expression profile
in the kidney of vitamin D receptor knockout mice.
J Cell Biochem 2003; 89: 709–719.
9. Freundlich M, Quiroz Y, Zhang Z et al. Suppression of
renin–angiotensin gene expression in the kidney by
paricalcitol. Kidney Int 2008; 74: 1394–1402.
10. Zhou C, Lu F, Cao K et al. Calcium-independent and
1,25(OH)
2
D
3
-dependent regulation of the renin-
angiotensin system in 1α-hydroxylase knockout
mice. Kidney Int 2008; 74: 170–179.
11. Zhang Z, Sun L, Wang Y et al. Renoprotective role
of the vitamin D receptor in diabetic nephropathy.
Kidney Int 2008; 73: 163–171.
12. Mizobuchi M, Morrissey J, Finch JL et al.
Combination therapy with an angiotensin-
converting enzyme inhibitor and a vitamin D
analog suppresses the progression of renal
insufficiency in uremic rats. J Am Soc Nephrol 2007;
18: 1796–1806.
13. Gilbert RE, Wu LL, Kelly DJ et al. Pathological
expression of renin and angiotensin II in the renal
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see original article on page 1403
Regulation of the Na
+
-Cl
cotransporter by dietary NaCl:
a role for WNKs, SPAK, OSR1,
and aldosterone
Volker Vallon
1,2,3
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
the Na
+
-Cl
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 eect 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
Na
+
-Cl
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
1
(this issue)
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
+
-K
+
-2Cl
cotransporter
(NKCC1), a member of a superfamily of
electroneutral cation-coupled chloride
cotransporters (SLC12) (reviewed by
Delpire and Gagnon
2
). e Na
+
-driven
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
2
). ese ndings
suggest that a signaling cascade includ-
ing WNK1, WNK4, and SPAK/OSR1
could be involved in the regulation of
the Na
+
-driven members of the SLC12
superfamily, including NCC.
WNK1 and WNK4 are mutated in
patients with pseudohypoaldosteronism
1
Department of Medicine, University of California,
San Diego, California, USA;
2
Department of
Pharmacology, University of California, San Diego,
California, USA; and
3
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.
E-mail: vvallon@ucsd.edu
    • "VDR has a ubiquitous tissue expression [6] and acts as a ligand-activated transcription factor [7] mediating most of the functions of its preferred ligand, 1,25-dihydroxyvitamin D [1,25(OH) 2 D]6789. The potential actions of 1,25(OH) 2 D expand far beyond its essential roles in calcium homeostasis and bone metabolism [6, 10], reaching highly diverse non-classical actions, such as regulation of cell proliferation and differentiation , immunomodulation, regulation of cytokine production and hormone secretion [9– 13]. Furthermore, 1,25(OH) 2 D inhibits various aspects of inflammation [14], a well-known key pathogenic mechanism of atherosclerosis, and protects against myocardial cell hyperthrophy [15] and fibrosis [16] , thus emerging as an important player in the protection against cardiovascular disease (CVD) mortality. "
    [Show abstract] [Hide abstract] ABSTRACT: Endothelial cell activation leading to leukocyte recruitment and adhesion plays an essential role in the initiation and progression of atherosclerosis. Vitamin D has cardioprotective actions, while its deficiency is a risk factor for the progression of cardiovascular damage. Our aim was to assess the role of basal levels of vitamin D receptor (VDR) on the early leukocyte recruitment and related endothelial cell-adhesion-molecule expression, as essential prerequisites for the onset of atherosclerosis. Knockdown of VDR in endothelial cells (shVDR) led to endothelial cell activation, characterized by upregulation of VCAM-1, ICAM-1 and IL-6, decreased peripheral blood mononuclear cell (PBMC) rolling velocity and increased PBMC rolling flux and adhesion to the endothelium. shVDR cells showed decreased IκBα levels and accumulation of p65 in the nucleus compared to shRNA controls. Inhibition of NF-κB activation with super-repressor IκBα blunted all signs of endothelial cell activation caused by downregulation of VDR in endothelial cells. In vivo, deletion of VDR led to significantly larger aortic arch and aortic root lesions in apoE-/- mice, with higher macrophage content. apoE-/-VDR-/-mice showed higher aortic expression of VCAM-1, ICAM-1 and IL-6 when compared to apoE-/-VDR+/+ mice. Our data demonstrate that lack of VDR signaling in endothelial cells leads to a state of endothelial activation with increased leukocyte-endothelial cell interactions that may contribute to the more severe plaque accumulation observed in apoE-/-VDR-/- mice. The results reveal an important role for basal levels of endothelial VDR in limiting endothelial cell inflammation and atherosclerosis.
    Full-text · Article · Aug 2015
    • "Vitamin D receptor agonists have been shown to inhibit renal inflammation and interstitial fibrosis in experimental models [18,42434445 and to reduce proteinuria and all-cause mortality121314151617 in chronic renal disease patients. Beyond the inhibition of renin–angiotensin system [18,4546474849, the beneficial effect of VDR activators seems attributable to their intrinsic anti-inflammatory properties [50,51]. VDR ligands, in fact, inhibit Th1 and Th17 cells and their related cytokines [52] and also chemokine production by target tissue cells53545556, particularly via inhibition of NF-kB activation [20,21,23,55,57]. "
    [Show abstract] [Hide abstract] ABSTRACT: During kidney allograft rejection, CXC chemokine ligand 10 (CXCL10)-CXC chemokine receptor 3 (CXCR3) trafficking between peripheral blood and tissues initiates alloresponse and perpetuates a self-inflammatory loop; thus, CXCL10-CXCR3 axis could represent a pharmacologic target. In this perspective, immunosuppressors targeting graft-resident cells, beside immune cells, could be very advantageous. Vitamin D receptor (VDR) agonists exhibit considerable immunomodulatory properties. This study aimed to investigate whether elocalcitol and BXL-01-0029 could decrease the expression of CXCL10 in activated renal tubular cells in vitro and thus be useful in kidney allograft rejection treatment. Experiments were performed in human tubular renal cells stimulated with interferon-gamma + tumor necrosis factor-alpha with and without VDR agonists, tacrolimus, sirolimus, hydrocortisone, methylprednisolone, cyclosporin A and mycophenolate mofetil. CXCL10 protein secretion and gene expression were measured by ELISA and by quantitative PCR. Specific inhibitors were used to investigate intracellular pathways involved in tubular cells activation. For IC(50) determination and comparison, dose-response curves with VDR agonists, tacrolimus and mycophenolic acid were performed. Elocalcitol and BXL-01-0029 inhibited CXCL10 secretion by renal cells, without affecting cell viability, while almost all the immunosuppressors were found to be ineffective, except for tacrolimus and mycophenolate mofetil. BXL-01-0029 was the most potent drug and, notably, it was found to be capable of allowing reduction in tacrolimus-inhibitory doses. Our data suggest that BXL-01-0029 could potentially be a dose-reducing agent for conventional immunosuppressors in kidney rejection management.
    Full-text · Article · Mar 2010
  • [Show abstract] [Hide abstract] ABSTRACT: Chronic kidney disease (CKD) is a common and costly medical condition, and currently available therapeutic options remain unsatisfactory. Vitamin D analogues are widely used for the bone and mineral disorder associated with CKD. However, accumulating evidence suggests that vitamin D analogues may have actions other than their effects on bone and mineral metabolism. In this article, we review the following aspects on the use of vitamin D analogues for the treatment of CKD: (1) epidemiological studies showing that patients with late-stage CKD have better survival than untreated patients; (2) animal studies showing that vitamin D analogues may retard the progression of CKD; (3) human studies on the anti-proteinuric and possibly renal protecting effects of vitamin D analogues in CKD and (4) the potential mechanisms of its therapeutic benefit. Nonetheless, definitive proof of the clinical benefits by randomized control trial would be necessary before one could advocate the routine use of vitamin D analogues for the treatment of CKD patients.
    Full-text · Article · May 2009
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