Expanding targets of vitamin D receptor activation: downregulation of several RAS components in the kidney
2008; Elsevier BV; Volume: 74; Issue: 11 Linguagem: Inglês
10.1038/ki.2008.424
ISSN1523-1755
Autores Tópico(s)Electrolyte and hormonal disorders
ResumoVitamin 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. 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. 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 immunomodulatory 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.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10653) Google Scholar and Andress2.Andress D.L. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation.Kidney Int. 2006; 69: 33-43Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar). 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.Achinger S.G. Ayus J.C. The role of vitamin D in left ventricular hypertrophy and cardiac function.Kidney Int Suppl. 2005: S37-S42Abstract Full Text Full Text PDF Scopus (96) Google Scholar 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.Kovesdy C.P. Kalantar-Zadeh K. Vitamin D receptor activation and survival in chronic kidney disease.Kidney Int. 2008; 73: 1355-1363Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar 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.Schmieder R.E. Hilgers K.F. Schlaich M.P. Schmidt B.M. Renin-angiotensin system and cardiovascular risk.Lancet. 2007; 369: 1208-1219Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar An inverse relationship between plasma calcitriol and renin activity was observed more than two decades ago in patients with essential hypertension.6.Resnick L.M. Muller F.B. Laragh J.H. Calcium-regulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism.Ann Intern Med. 1986; 105: 649-654Crossref PubMed Scopus (382) Google Scholar In concert with these seminal findings, mice lacking the VDR and mice with inhibited calcitriol synthesis showed hypertension, increased renal expression of renin, elevated angiotensin II (AngII) levels, and cardiac hypertrophy.7.Li Y.C. 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: 229-238Crossref PubMed Scopus (1753) Google Scholar Today a widely accepted concept is that VDR activation is a negative endocrine regulator of renin expression in the kidney independent of calcium metabolism. VDR activation regulates the expression of a large number of genes in the kidney.8.Li X. Zheng W. Li Y.C. Altered gene expression profile in the kidney of vitamin D receptor knockout mice.J Cell Biochem. 2003; 89: 709-719Crossref PubMed Scopus (44) Google Scholar The results of Freundlich and co-workers9.Freundlich M. Quiroz Y. Zhang Z. et al.Suppression of renin–angiotensin gene expression in the kidney by paricalcitol.Kidney Int. 2008; 74: 1394-1402Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar (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 (AT1R). 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.Andress D.L. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation.Kidney Int. 2006; 69: 33-43Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar,4.Kovesdy C.P. Kalantar-Zadeh K. Vitamin D receptor activation and survival in chronic kidney disease.Kidney Int. 2008; 73: 1355-1363Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar The findings of Freundlich and co-workers9.Freundlich M. Quiroz Y. Zhang Z. et al.Suppression of renin–angiotensin gene expression in the kidney by paricalcitol.Kidney Int. 2008; 74: 1394-1402Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar 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 AngII, and aldosterone concentrations, as well as renin and angiotensinogen mRNA levels and renin protein levels in the kidney.10.Zhou C. Lu F. Cao K. et al.Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1α-hydroxylase knockout mice.Kidney Int. 2008; 74: 170-179Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar 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.Zhang Z. Sun L. Wang Y. et al.Renoprotective role of the vitamin D receptor in diabetic nephropathy.Kidney Int. 2008; 73: 163-171Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar 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 angiotensin-converting enzyme inhibition.12.Mizobuchi M. Morrissey J. Finch J.L. 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: 1796-1806Crossref PubMed Scopus (182) Google Scholar The experiment design did not include a sham-operated group treated with paricalcitol.9.Freundlich M. Quiroz Y. Zhang Z. et al.Suppression of renin–angiotensin gene expression in the kidney by paricalcitol.Kidney Int. 2008; 74: 1394-1402Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar As the treatment already started 4 days after surgery, the possibility 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.Li Y.C. 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: 229-238Crossref PubMed Scopus (1753) Google Scholar 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.Zhou C. Lu F. Cao K. et al.Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1α-hydroxylase knockout mice.Kidney Int. 2008; 74: 170-179Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar,11.Zhang Z. Sun L. Wang Y. et al.Renoprotective role of the vitamin D receptor in diabetic nephropathy.Kidney Int. 2008; 73: 163-171Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar The cell types responsible for the differences in RAS component expression after VDR activation remain unknown.9.Freundlich M. Quiroz Y. Zhang Z. et al.Suppression of renin–angiotensin gene expression in the kidney by paricalcitol.Kidney Int. 2008; 74: 1394-1402Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar 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.Gilbert R.E. Wu L.L. Kelly D.J. 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: 429-440Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar 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 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.Schmieder R.E. Hilgers K.F. Schlaich M.P. Schmidt B.M. Renin-angiotensin system and cardiovascular risk.Lancet. 2007; 369: 1208-1219Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar 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.Andress D.L. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation.Kidney Int. 2006; 69: 33-43Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar and the influence of VDR activation on several RAS components remains to be elucidated (Figure 1). 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.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10653) Google Scholar 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.Kovesdy C.P. Kalantar-Zadeh K. Vitamin D receptor activation and survival in chronic kidney disease.Kidney Int. 2008; 73: 1355-1363Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar 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.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10653) Google Scholar,2.Andress D.L. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation.Kidney Int. 2006; 69: 33-43Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar 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 ongoing randomized clinical trials on the effects of VDR activation on renal failure-induced 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.Freundlich M. Quiroz Y. Zhang Z. et al.Suppression of renin–angiotensin gene expression in the kidney by paricalcitol.Kidney Int. 2008; 74: 1394-1402Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar 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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