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

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http://www.kidney-international.org © 2008 International Society of Nephrology

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

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.

Ilkka H. Pörsti1

VDR activation regulates the expression of a large number of genes in the kidney.8 The results of Freundlich and co-workers9 (this issue) indicate that the effects of VDR activation on RAS components are not limited to reduced expression of renin. In 5/6 nephrectomized rats, treatment with pari­calcitol was associated with suppression of several RAS components in the kidney: renin, renin receptor, angiotensinogen, and Ang II type  1 receptor (AT 1R). 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 important mechanism to reduce fibrogenesis in the kidney. It is of note that calcitriol can inhibit matrix-producing interstitial myofibroblast activation via upregulation of antifibrotic hepatocyte growth factor gene expression, and that VDR activation may exert renoprotective activity by suppressing inflammatory-cell infiltration and inhibiting nuclear factor-κB activation. The lack of VDR activation may thus also result in increased susceptibility to inflammatory stimulation.2,4 The findings of Freundlich and coworkers9 are supported by recent observations in mice made deficient 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 aldosterone concentrations, as well as renin and

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 regulation of calcium homeostasis and bone mineralization via vitamin D receptor (VDR) activation but also has antiproliferative, pro-differentiation, and immuno­ modulatory activities. The 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 diseases. The vitamin D endocrine system also participates in the regulation of blood pressure, volume homeostasis, cardiac function, and protection of renal cellular integrity (reviewed by Holick1 and Andress2). 1Medical 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: [email protected]

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It seems clear that the altered vitamin D status contributes to the cardiovascular pathology in chronic renal insufficiency, with associated changes in the function of various tissues, including vascular smooth muscle and the heart. In hemodialysis patients, the treatment of secondary hyperparathyroidism by calcitriol has been suggested to induce regression of myocardial hypertrophy. A reduced calcitriol level may also contribute to the enhanced fibrogenesis in chronic renal insufficiency.3 The nonclassical mechanisms 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 The local intrarenal renin–angiotensin system (RAS) is an important determinant of kidney tissue injury, inflammation, 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 findings, mice lacking the VDR and mice with inhibited calcitriol synthesis showed hypertension, increased renal expression of renin,



Vitamin D receptor activation and the renal renin–angiotensin system

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Renin

Angiotensin-converting enzyme ±

Renin/prorenin receptor

mas oncogene?

Angiotensinogen

VDR activation

AT4 receptor? Angiotensin(1–7)?

Angiotensin II

AT1 receptor

AT2 receptor?

Angiotensin-converting enzyme 2?

Angiotensin(1–12)?

Figure 1 | Established or newly suggested effects of vitamin D receptor activation on the components of the renin–angiotensin system.

angiotensinogen mRNA levels and renin protein levels in the kidney.10 Another interesting report, by Zhang and coworkers, 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. The inhibition of the RAS by medical compounds is often referred to as being renoprotective, but despite active drug treatment, the course of many renal diseases can only be slowed down, not prevented. Therefore, all additional treatment modalities are welcome, and VDR activation may be one such approach. Supporting a synergistic action between VDR activation and pharmacological RAS blockade, paricalcitol treatment was found to retard the progression of experimental renal insufficiency via an effect on the TGF-β signaling pathway, and this effect was amplified with simultaneous angiotensinconverting enzyme inhibition.12 Some remarks on study limitations

The experiment design did not include a sham-operated group treated with paricalcitol.9 As the treatment already started 4 days after surgery, the possibility 1372

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 The reports of activated RAS in VDR knockout mice, and in mice with targeted ablation of the 1α-(OH)ase gene, indicate that renal ablation is not a prerequisite for VDR activation to influence RAS components.10,11 The cell types responsible for the differences in RAS component expression after VDR activation remain unknown.9 Following renal mass reduction there is suppressed juxtaglomerular renin synthesis 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 inhibition.13 Renal AT1R 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 influenced the pathological expression of RAS components following 5/6 nephrectomy. The renin–angiotensin system: increasing complexity

The RAS is becoming ever more complex and the number of its known components

higher, and the same holds true for the number of RAS regulators. VDR activation has established or newly suggested effects on renin, angiotensinogen, Ang II, AT1R, and renin receptor, but the influences remain unknown on Ang II type 2 and type 4 receptors (AT2R and AT4R), angiotensin-converting enzyme 2, and the angiotensin(1–7) receptor mas oncogene, which contribute to cardiovascular function and growth.5 Via reduction of renin and angiotensinogen, VDR activation also has the potential to influence the levels of angiotensin(1–7) and the novel angiotensin precursor angiotensin(1–12), formed from angiotensinogen via non-renin mechanisms. VDR can cross-talk with diverse cellular signals by forming complexes with a wide variety of transcription factors,2 and the influence 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 activation and RAS inhibition carries interesting therapeutic potential. Low vitamin D status is common not only in patients with chronic kidney disease but also in the general population.1 The findings on RAS favor a more active treatment with VDR activators in chronic kidney disease patients. However, the use of VDR analogues appears to suppress endogenous calcitriol levels in plasma, but what happens in the long term at the tissue level is unknown. This may be important, as calcitriol and activated vitamin D analogues may differ in their ancillary effects, and some of the ancillary effects may favor the analogues, but others may favor calcitriol.4 The 1α-(OH)ase is widely distributed, and local calcitriol synthesis from calcidiol may play an important role in regulation of various cellular processes in different 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 influence RAS components in vivo in humans with VDR activators without side effects; does this have an influence on the progression of renal disease; and what doses are needed? The Kidney International (2008) 74

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ongoing randomized clinical trials on the effects of VDR activation on renal failureinduced cardiac mortality and the progression of albuminuria (PRIMO and VITAL) seem highly warranted, and we are awaiting the results. The present results of Freundlich 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.

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Regulation of the Na+-Cl– cotransporter by dietary NaCl: a role for WNKs, SPAK, OSR1, and aldosterone Volker Vallon1,2,3 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

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Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266–281. Andress DL. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int 2006; 69: 33–43. Achinger SG, Ayus JC. The role of vitamin D in left ventricular hypertrophy and cardiac function. Kidney Int Suppl 2005; S37–S42. Kovesdy CP, Kalantar-Zadeh K. Vitamin D receptor activation and survival in chronic kidney disease. Kidney Int 2008; 73: 1355–1363. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet 2007; 369: 1208–1219. Resnick LM, Muller FB, Laragh JH. Calciumregulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986; 105: 649–654. 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. 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. 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. Zhou C, Lu F, Cao K et al. Calcium-independent and 1,25(OH)2D3-dependent regulation of the reninangiotensin system in 1α-hydroxylase knockout mice. Kidney Int 2008; 74: 170–179. Zhang Z, Sun L, Wang Y et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 2008; 73: 163–171. Mizobuchi M, Morrissey J, Finch JL et al. Combination therapy with an angiotensinconverting enzyme inhibitor and a vitamin D analog suppresses the progression of renal insufficiency in uremic rats. J Am Soc Nephrol 2007; 18: 1796–1806. Gilbert RE, Wu LL, Kelly DJ et al. Pathological expression of renin and angiotensin II in the renal tubule after subtotal nephrectomy. Implications for the pathogenesis of tubulointerstitial fibrosis. Am J Pathol 1999; 155: 429–440.

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An impaired ability of the kidney to excrete NaCl plays a critical pathophysiological role for a long-term increase in blood pressure. The aldosterone-sensitive distal nephron is of primary importance in the regulation of renal NaCl excretion and thus body NaCl homeostasis. The stimulatory effect of aldosterone 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 regulators. 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. The study by Chiga and co-workers1 (this issue) provides new in vivo evidence in this regard, as they indicate an important role of aldosterone in the regulation of 1Department of Medicine, University of California,

San Diego, California, USA; 2Department of Pharmacology, University of California, San Diego, California, USA; and 3VA 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: [email protected]



NCC phosphorylation by dietary salt intake. Moreover, evidence is provided that the signaling cascade involves withno-lysine kinase (WNK) and the mammalian STE20 (sterile 20)-like kinases SPAK (STE20/SPS1-related proline/ alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase-1). SPAK and OSR1 were discovered through their ability to interact with, phosphorylate, and stimulate the activity of the Na +-K+-2Cl – cotransporter (NKCC1), a member of a superfamily of electroneutral cation-coupled chloride cotransporters (SLC12) (reviewed by Delpire and Gagnon2). The Na+-driven members of this superfamily include NKCC1 and NKCC2, as well as NCC. Fragments of these cotransporters containing a cluster of conserved threonine residues are phosphorylated in vitro by the SPAK/OSR1 kinases. The SPAK and OSR1 enzymes themselves are phosphorylated and activated by the WNK1 and WNK4 protein kinases (reviewed by Delpire and Gagnon2). These findings suggest that a signaling cascade including 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 1373