Renoprotective role of the vitamin D receptor in diabetic nephropathy
2007; Elsevier BV; Volume: 73; Issue: 2 Linguagem: Inglês
10.1038/sj.ki.5002572
ISSN1523-1755
AutoresZ. Zhang, Lin Sun, Yanbin Wang, Gang Ning, Andrew W. Minto, Jiming Kong, Richard J. Quigg, Y.C. Li,
Tópico(s)Hormonal Regulation and Hypertension
Resumo1,25-Dihydroxyvitamin D3 negatively regulates the renin–angiotensin system (RAS), which plays a critical role in the development of diabetic nephropathy. We tested if mice lacking the vitamin D receptor (VDR) are more susceptible to hyperglycemia-induced renal injury. Diabetic VDR knockout mice developed more severe albuminuria and glomerulosclerosis due to increased glomerular basement membrane thickening and podocyte effacement. More fibronectin (FN) and less nephrin were expressed in the VDR knockout mice compared to diabetic wild-type mice. In receptor knockout mice, increased renin, angiotensinogen, transforming growth factor-β (TGF-β), and connective tissue growth factor accompanied the more severe renal injury. 1,25-Dihydroxyvitmain D3 inhibited high glucose (HG)-induced FN production in cultured mesangial cells and increased nephrin expression in cultured podocytes. 1,25-Dihydroxyvitmain D3 also suppressed HG-induced activation of the RAS and TGF-β in mesangial and juxtaglomerular cells. Our study suggests that receptor-mediated vitamin D actions are renoprotective in diabetic nephropathy. 1,25-Dihydroxyvitamin D3 negatively regulates the renin–angiotensin system (RAS), which plays a critical role in the development of diabetic nephropathy. We tested if mice lacking the vitamin D receptor (VDR) are more susceptible to hyperglycemia-induced renal injury. Diabetic VDR knockout mice developed more severe albuminuria and glomerulosclerosis due to increased glomerular basement membrane thickening and podocyte effacement. More fibronectin (FN) and less nephrin were expressed in the VDR knockout mice compared to diabetic wild-type mice. In receptor knockout mice, increased renin, angiotensinogen, transforming growth factor-β (TGF-β), and connective tissue growth factor accompanied the more severe renal injury. 1,25-Dihydroxyvitmain D3 inhibited high glucose (HG)-induced FN production in cultured mesangial cells and increased nephrin expression in cultured podocytes. 1,25-Dihydroxyvitmain D3 also suppressed HG-induced activation of the RAS and TGF-β in mesangial and juxtaglomerular cells. Our study suggests that receptor-mediated vitamin D actions are renoprotective in diabetic nephropathy. In both type I and type II diabetic mellitus, diabetic nephropathy is the most common renal complication that often leads to end-stage kidney disease with its attendant renal failure and high mortality.1.Ritz E. Rychlik I. Locatelli F. et al.End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions.Am J Kidney Dis. 1999; 34: 795-808Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar Diabetic nephropathy is a long-term complication, characterized initially by glomerular and tubuloepithelial hypertrophy, and thickening of glomerular and tubular basement membranes, followed by hyperfiltration, albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, leading eventually to end-stage kidney disease.2.Cooper M.E. Pathogenesis, prevention, and treatment of diabetic nephropathy.Lancet. 1998; 352: 213-219Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar The pathogenesis of diabetic nephropathy is complex and involves direct actions of extracellular glucose on glomerular, tubular, vascular, and interstitial cells. These actions lead to the stimulation of cytokines and growth factors, such as angiotensin II (Ang II), transforming growth factor-β (TGF-β), and monocyte chemoattractant protein (MCP)-1, which play a major role in the development of diabetic nephropathy.3.Carey R.M. Siragy H.M. The intrarenal renin–angiotensin system and diabetic nephropathy.Trends Endocrinol Metab. 2003; 14: 274-281Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 4.Ziyadeh F.N. Mediators of diabetic renal disease: the case for tgf-beta as the major mediator.J Am Soc Nephrol. 2004; 15: S55-S57Crossref PubMed Google Scholar, 5.Banba N. Nakamura T. Matsumura M. et al.Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy.Kidney Int. 2000; 58: 684-690Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar The renin–angiotensin system (RAS) has been implicated as a major mediator of progressive renal injury in diabetic nephropathy. Clinical studies demonstrated that treatment with angiotensin-converting enzyme inhibitors or Ang II type 1 receptor blockers can reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria.6.Chan J.C. Ko G.T. Leung D.H. et al.Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.Kidney Int. 2000; 57: 590-600Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 7.Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, 8.Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 9.Parving H.H. Lehnert H. Brochner-Mortensen J. et al.The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2845) Google Scholar, 10.Andersen S. Tarnow L. Rossing P. et al.Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy.Kidney Int. 2000; 57: 601-606Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Because the systemic components of the RAS are actually downregulated in diabetic mellitus,11.Price D.A. Porter L.E. Gordon M. et al.The paradox of the low-renin state in diabetic nephropathy.J Am Soc Nephrol. 1999; 10: 2382-2391PubMed Google Scholar whereas renal interstitial Ang II levels are 1000-fold higher than in the plasma,12.Nishiyama A. Seth D.M. Navar L.G. Renal interstitial fluid concentrations of angiotensins I and II in anesthetized rats.Hypertension. 2002; 39: 129-134Crossref PubMed Scopus (191) Google Scholar intrarenal RAS is believed to play the major damaging role. Indeed, all components of the RAS are present within the kidney.13.Navar L.G. Inscho E.W. Majid S.A. et al.Paracrine regulation of the renal microcirculation.Physiol Rev. 1996; 76: 425-536PubMed Google Scholar Kidney cells synthesize renin, renin receptor,14.Nguyen G. Delarue F. Burckle C. et al.Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.J Clin Invest. 2002; 109: 1417-1427Crossref PubMed Scopus (1136) Google Scholar angiotensinogen, and Ang II receptors independent of the systemic RAS,15.Lavoie J.L. Sigmund C.D. Minireview: overview of the renin–angiotensin system—an endocrine and paracrine system.Endocrinology. 2003; 144: 2179-2183Crossref PubMed Scopus (397) Google Scholar making the kidney capable of maintaining high intrarenal Ang II levels. In fact, intrarenal renin and angiotensinogen levels are increased in diabetic animals,16.Anderson S. Jung F.F. Ingelfinger J.R. Renal renin–angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations.Am J Physiol. 1993; 265: F477-F486PubMed Google Scholar,17.Zimpelmann J. Kumar D. Levine D.Z. et al.Early diabetes mellitus stimulates proximal tubule renin mRNA expression in the rat.Kidney Int. 2000; 58: 2320-2330Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar and high glucose (HG) is known to stimulate renin and Ang II synthesis in mesangial cells (MCs).18.Singh R. Singh A.K. Alavi N. et al.Mechanism of increased angiotensin II levels in glomerular mesangial cells cultured in high glucose.J Am Soc Nephrol. 2003; 14: 873-880Crossref PubMed Scopus (119) Google Scholar,19.Vidotti D.B. Casarini D.E. Cristovam P.C. et al.High glucose concentration stimulates intracellular renin activity and angiotensin II generation in rat mesangial cells.Am J Physiol Renal Physiol. 2004; 286: F1039-F1045Crossref PubMed Scopus (172) Google Scholar Intrarenal Ang II has multiple effects that can contribute to the progression of renal injury, such as increasing glomerular capillary pressure and permeability (leading to proteinuria), stimulation of renal cell proliferation and hypertrophy, synthesis of cytokines and extracellular matrix (ECM) and promotion of macrophage infiltration and inflammation.3.Carey R.M. Siragy H.M. The intrarenal renin–angiotensin system and diabetic nephropathy.Trends Endocrinol Metab. 2003; 14: 274-281Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar,20.Gilbert R.E. Krum H. Wilkinson-Berka J. et al.The renin–angiotensin system and the long-term complications of diabetes: pathophysiological and therapeutic considerations.Diabet Med. 2003; 20: 607-621Crossref PubMed Scopus (69) Google Scholar Consistent with a destructive role of the intrarenal RAS, transgenic rats overexpressing renin with streptozotocin (STZ)-induced diabetes develop more severe diabetic nephropathy.21.Kelly D.J. Wilkinson-Berka J.L. Allen T.J. et al.A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR).Kidney Int. 1998; 54: 343-352Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, is an endocrine hormone with multiple physiological functions. We have demonstrated that 1,25(OH)2D3 functions as a negative endocrine regulator of the RAS.22.Li Y.C. Qiao G. Uskokovic M. et al.Vitamin D: a negative endocrine regulator of the renin–angiotensin system and blood pressure.J Steroid Biochem Mol Biol. 2004; 89–90: 387-392Crossref PubMed Scopus (433) Google Scholar 1,25(OH)2D3 suppresses renin biosynthesis, and null-mutant mice lacking the vitamin D receptor (VDR) gene develop hyperreninemia, high blood pressure, and cardiac hypertrophy.23.Xiang W. Kong J. Chen S. et al.Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin–angiotensin systems.Am J Physiol Endocrinol Metab. 2005; 288: E125-E132Crossref PubMed Scopus (480) Google Scholar, 24.Kong J. Li Y.C. Effect of angiotensin II type I receptor antagonist and angiotensin-converting enzyme inhibitor on vitamin d receptor null mice.Am J Physiol Regul Integr Comp Physiol. 2003; 285: R255-R261Crossref PubMed Scopus (73) Google Scholar, 25.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 (1614) Google Scholar Low-calcemic vitamin D analogs are also able to inhibit renin expression in animals.26.Qiao G. Kong J. Uskokovic M. et al.Analogs of 1alpha,25-dihydroxyvitamin D3 as novel inhibitors of renin biosynthesis.J Steroid Biochem Mol Biol. 2005; 96: 59-66Crossref PubMed Scopus (71) Google Scholar Given the crucial role of the RAS in the development of diabetic nephropathy, we speculate that vitamin D deficiency, which can lead to activation of the RAS, may increase the susceptibility to hyperglycemia-induced renal injury. Here we show that VDR knockout mice develop more severe diabetic nephropathy. Our data support the notion that vitamin D plays a renoprotective role against renal injury by regulation of the RAS and other genes involved in renal injury. We used VDR−/− mice to test the hypothesis that vitamin D has renoprotective activity and can ameliorate renal injury in diabetic nephropathy. We reasoned that if vitamin D provides renal protection, then mice lacking the VDR could be more susceptible to hyperglycemia-induced renal injury. We used the STZ-induced diabetes model, and followed the mice for up to 19 weeks. As shown in Figure 1, the blood glucose level rose to around 450 mg dl−1 in both VDR+/+ and VDR−/− mice 2 weeks after STZ treatment, and hyperglycemia persisted during the 19-week period (Figure 1a); both VDR+/+ and VDR−/− mice exhibited a mild reduction of body weight during this time (data not shown). As expected, both VDR+/+ and VDR−/− mice developed albuminuria (expressed as urinary albumin to creatinine ratio (ACR)), and the severity increased with time (Figure 1b). Remarkably, not only was the ACR significantly higher in VDR−/− mice compared to VDR+/+ mice, but the increase of ACR was also more robust in VDR−/− mice, with marked elevation seen at as early as 5–7 weeks after STZ injection. Of note, non-diabetic VDR−/− mice had similar blood glucose levels as VDR+/+ mice (81.5±8.4 vs 97±8.2 mg dl−1 at 7 months of age, n=5). The urinary albumin levels were similar in young non-diabetic VDR+/+ and VDR−/− mice, and VDR−/− mice tended to have higher urinary albumin excretion than VDR+/+ mice when aging (ACR: 216±85 vs 169±86 at 5 months of age, n=4). Thus, diabetic VDR−/− mice appeared to develop earlier and more severe albuminuria compared to their VDR+/+ counterparts. Histological examination of the kidney revealed that diabetic VDR−/− mice developed more severe glomerulosclerosis than diabetic VDR+/+ mice at week 19, manifested by more ECM accumulation in the mesangium (Figure 2a). In comparison, ECM accumulation in non-diabetic VDR+/+ and VDR−/− mice was minimal (Figure 2a). Semiquantitative scoring of the kidney sections confirmed this observation (Figure 2b). Consistently, the expression of fibronectin (FN), one of the major ECM proteins, was also higher in VDR−/− mice than in VDR+/+ mice, as determined by immunofluorescent staining (Figure 2c) and western blotting (Figure 2d and e). We also measured the protein level of podocin and nephrin in kidney lysates from the two groups of mice by western blotting. Whereas the level of podocin was similar, nephrin was significantly reduced in VDR−/− mice at week 19 (Figure 3a–c). This is consistent with the more severe albuminuria phenotype observed in VDR−/− mice, as nephrin is a key component of the slit diaphragm of the glomerular filtration barrier and plays a critical role in the regulation of protein filtration.27.Kestila M. Lenkkeri U. Mannikko M. et al.Positionally cloned gene for a novel glomerular protein–nephrin—is mutated in congenital nephrotic syndrome.Mol Cell. 1998; 1: 575-582Abstract Full Text Full Text PDF PubMed Scopus (1480) Google ScholarFigure 3Expression of podocin and nephrin in diabetic mice. (a) Western blot analyses of podocin and nephrin protein in kidney lysates from STZ-treated VDR+/+ and VDR−/− mice at week 19. Densitometric quantification of (b) podocin and (c) nephrin levels in these mice. *P 4-fold, Figure 5a), angiotensinogen (>6-fold, Figure 5b), and Ang II type 1 receptor (AT1R, fourfold, Figure 5c) in VDR+/+ mice. The increase of the RAS in VDR−/− mice was more robust. As has been shown previously,25.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 (1614) Google Scholar the basal level of renin in non-diabetic VDR−/− mice was already upregulated. In diabetic VDR−/− mice, the renin mRNA level was further increased (Figure 5a), even though the induction over the VDR−/− baseline was similar in comparison to VDR+/+ mice. Similarly, angiotensinogen and AT1R were also induced to a higher level in diabetic VDR−/− mice (Figure 5b and c). The more robust increase in renin mRNA in the kidney of diabetic VDR−/− mice was also detected by northern blot analysis (Figure 5d). Moreover, immunostaining of the kidney sections confirmed a more robust induction at renin protein levels in the juxtaglomerular apparatus of VDR−/− mice (Figure 5e); AT1R protein was also increased more in diabetic VDR−/− mice than in diabetic VDR+/+ mice, mostly in the cytoplasm of tubular epithelial cells (Figure 5f). Little staining was seen in the non-diabetic mice. The level of ACE was not significantly altered in diabetic mice (data not shown). Therefore, the enhanced renal injury observed in diabetic VDR−/− mice was accompanied by an apparently higher degree of RAS induction. It has been implicated that TGF-β and connective tissue growth factor (CTGF) play important roles in the development of glomerular sclerosis;4.Ziyadeh F.N. Mediators of diabetic renal disease: the case for tgf-beta as the major mediator.J Am Soc Nephrol. 2004; 15: S55-S57Crossref PubMed Google Scholar,28.Gupta S. Clarkson M.R. Duggan J. et al.Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis.Kidney Int. 2000; 58: 1389-1399Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar therefore, we also compared the expression of TGF-β and CTGF in diabetic VDR+/+ and VDR−/− mice by real-time RT-PCR analyses. There was a modest increase in renal TGF-β mRNA expression in diabetic mice compared with non-diabetic mice, with the induction in diabetic VDR−/− mice (50%) higher than in diabetic VDR+/+ mice (20%) (Figure 6a). Renal CTGF mRNA levels were similarly induced over the baseline in diabetic VDR+/+ and VDR−/− mice; however, the basal CTGF level was already elevated in non-diabetic VDR−/− mice, and hence, CTGF expression was increased to a higher level in diabetic VDR−/− mice than the VDR+/+ counterparts (Figure 6b). These data are consistent with the more severe glomerular phenotype in the mutant mice. The development of more severe glomerular abnormalities in diabetic VDR−/− mice suggests a protective role of vitamin D against renal injury in diabetic nephropathy. To explore the molecular basis, we utilized in vitro cell cultures to investigate the effect of vitamin D. MCs are the major component of the glomerular mesangium that provides structural support for the glomerular capillary. Hyperglycemia-stimulated ECM overproduction by MCs leads to glomerulosclerosis in diabetic nephropathy.29.van Dijk C. Berl T. Pathogenesis of diabetic nephropathy.Rev Endocr Metab Disord. 2004; 5: 237-248Crossref PubMed Scopus (35) Google Scholar In MC cultures, HG (30 mM) markedly induced FN expression at both the mRNA and protein levels, and this stimulation was suppressed by 1,25(OH)2D3 in a dose-dependent manner (Figure 7a). As a result, FN synthesis was virtually normalized at 10−7 M. Immunostaining with anti-FN antibody confirmed that 1,25(OH)2D3 blocked the HG-induced FN induction (Figure 7b). We also examined the effect of HG and vitamin D on the RAS in cell cultures. As shown in Figure 8, a low level of renin was detected in MCs by RT-PCR, which was increased by approximately twofold by HG; the induction was blocked in the presence of 1,25(OH)2D3 (Figure 8a). Similar results were observed in As4.1 cells, a juxtaglomerular cell line expressing a high level of renin, in which 1,25(OH)2D3 reversed the HG induction of renin expression in a dose-dependent manner (Figure 8e). HG also dramatically increased the expression of angiotensinogen (by >5-fold) and AT1R (by >6-fold) in MCs, and 1,25(OH)2D3 markedly inhibited the increase of these gene expressions (Figure 8c and d). Consistent with the animal data, no changes were seen in the expression of ACE in the presence of HG or 1,25(OH)2D3 (Figure 8b). In MCs, HG also induced TGF-β expression, and the induction was partially suppressed by 1,25(OH)2D3 (Figure 9a). In podocytes, HG decreased nephrin expression by approximately 25%, and 1,25(OH)2D3 dose dependently stimulated nephrin mRNA expression (Figure 9b), suggesting that nephrin may be a direct target of vitamin D regulation. This is consistent with the in vivo data showing a lower nephrin expression in diabetic VDR−/− mice (Figure 3). It is well established that the vitamin D endocrine system functions beyond the regulation of calcium and phosphate metabolism. Emerging clinical and animal studies have revealed pivotal protective roles of vitamin D in the renal and cardiovascular systems.30.Levin A. Li Y.C. Vitamin D and its analogues: do they protect against cardiovascular disease in patients with kidney disease?.Kidney Int. 2005; 68: 1973-1981Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar Vitamin D/vitamin D analog therapy offers significant survival advantage for patients with chronic kidney disease, with improvement in renal and cardiovascular functions.31.Teng M. Wolf M. Lowrie E. et al.Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.N Engl J Med. 2003; 349: 446-456Crossref PubMed Scopus (851) Google Scholar, 32.Shoji T. Shinohara K. Kimoto E. et al.Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population.Nephrol Dial Transplant. 2004; 19: 179-184Crossref PubMed Scopus (332) Google Scholar, 33.Teng M. Wolf M. Ofsthun M.N. et al.Activated injectable vitamin D and hemodialysis survival: a historical cohort study.J Am Soc Nephrol. 2005; 16: 1115-1125Crossref PubMed Scopus (713) Google Scholar A recent clinical trial shows that paricalcitol, an activated vitamin D analog, can reduce proteinuria in chronic kidney disease patients.34.Agarwal R. Acharya M. Tian J. et al.Antiproteinuric effect of oral paricalcitol in chronic kidney disease.Kidney Int. 2005; 68: 2823-2828Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar In subtotally nephrectomized rats, administration of 1,25(OH)2D3 significantly decreased albuminuria, podocyte hypertrophy, and glomerulosclerosis.35.Kuhlmann A. Haas C.S. Gross M.L. et al.1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat.Am J Physiol Renal Physiol. 2004; 286: F526-F533Crossref PubMed Scopus (199) Google Scholar 22-Oxacalcitriol, a low-calcemic vitamin D analog, inhibited MC proliferation in vitro36.Abe H. Iehara N. Utsunomiya K. et al.A vitamin D analog regulates mesangial cell smooth muscle phenotypes in a transforming growth factor-beta type II receptor-mediated manner.J Biol Chem. 1999; 274: 20874-20878Crossref PubMed Scopus (30) Google Scholar and ameliorated glomerular injury in rats with glomerulonephritis.37.Makibayashi K. Tatematsu M. Hirata M. et al.A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis.Am J Pathol. 2001; 158: 1733-1741Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar However, to our knowledge, the effect of vitamin D on the development of diabetic nephropathy has not been reported. Our data obtained from this investigation are consistent with the notion that vitamin D plays a renoprotective role against renal injury in diabetic mice.38.Wang Y. Zhou J. Minto A.W. et al.Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy.Kidney Int. 2006; 70: 882-891Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In this study, we demonstrated that mice lacking VDR develop more severe diabetic nephropathy compared to wild-type mice. The pathological hallmarks of diabetic nephropathy include proteinuria and glomerulosclerosis,2.Cooper M.E. Pathogenesis, prevention, and treatment of diabetic nephropathy.Lancet. 1998; 352: 213-219Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar and both are more severe in diabetic VDR knockout mice. Despite similar levels of hyperglycemia in wild-type and VDR knockout mice, albuminuria was markedly more severe with an earlier onset in VDR knockout mice compared to wild-type mice. This finding is particularly interesting because it is consistent with a recent clinical observation that vitamin D analog reduced proteinuria in chronic kidney disease patients.34.Agarwal R. Acharya M. Tian J. et al.Antiproteinuric effect of oral paricalcitol in chronic kidney disease.Kidney Int. 2005; 68: 2823-2828Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar Severe albuminuria was accompanied by increased GBM thickness and decreased nephrin expression in VDR knockout mice. The effect of VDR ablation on podocytes is consistent with an early study showing that vitamin D can prevent the loss of podocytes and reduce podocyte injury in nephrectomized rats.35.Kuhlmann A. Haas C.S. Gross M.L. et al.1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat.Am J Physiol Renal Physiol. 2004; 286: F526-F533Crossref PubMed Scopus (199) Google Scholar On the other hand, accumulation of mesangial extracellular matrix is also more prominent in VDR knockout mice, with higher FN expression. These results suggest that mice are more susceptible to hyperglycemia-induced renal injury in the absence of VDR or in vitamin D deficiency, supporting a protective role of VDR in diabetic nephropathy. Vitamin D has several important activities that may contribute to its renoprotective property. These activities include inhibition of profibrotic growth factors and inflammatory cytokines and suppression of the RAS. First, 1,25(OH)2D3 may target TGF-β and CTGF, known as important mediators for the development of sclerosis in diabetic nephropathy.4.Ziyadeh F.N. Mediators of diabetic renal disease: the case for tgf-beta as the major mediator.J Am Soc Nephrol. 2004; 15: S55-S57Crossref PubMed Google Scholar, 28.Gupta S. Clarkson M.R. Duggan J. et al.Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis.Kidney Int. 2000; 58: 1389-1399Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar, 39.Goldschmeding R. Aten J. Ito Y. et al.Connective tissue growth factor: just another factor in renal fibrosis?.Nephrol Dial Transplant. 2000; 15: 296-299Crossref PubMed Scopus (74) Google Scholar 1,25(OH)2D3 is known to downregulate TGF-β signaling by suppressing Smad3 expression in renal tissue40.Aschenbrenner J.K. Sollinger H.W. Becker B.N. et al.1,25-(OH(2))D(3) alters the transforming growth factor beta signaling pathway in renal tissue.J Surg Res. 2001; 100: 171-175Abstract Full Text PDF PubMed Scopus (58) Google Scholar or by inducing VDR physical interaction with Smad3 protein;41.Yanagisawa J. Yanagi Y. Masuhiro Y. et al.Convergence of transforming growth factor-beta and vitamin D signaling pathways on SMAD transcriptional coactivators.Science. 1999; 283: 1317-1321Crossref PubMed Scopus (405) Google Scholar therefore, VDR ablation may increase Smad3 activity. This, in conjunction with the increase in TGF-β levels, will lead to more active TGF-β signaling in VDR−/− mice. Vitamin D is likely a suppressor of CTGF synthesis; higher CTGF levels also contribute to the fibrogenic potential in diabetic VDR knockout mice. Most recently we demonstrated that vitamin D also regulates MCP-1, an inflammatory cytokine that stimulates macrophage infiltration into the kidney, to ameliorate renal injury.42.Zhang Z. Yuan W. Sun L. et al.1,25-Dihydroxyvitamin D3 suppresses high glucose-induced MCP-1 expression in mesangial cells by targeting NF-kappaB.Kidney Int. 2007; 72: 193-201Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar In addition, 1,25(OH)2D3 may also directly inhibit HG-induced FN expression and stimulate nephrin expression. Second, the renoprotective property of vitamin D may also be attributed to its regulation of the RAS, particularly renin.25.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 (1614) Google Scholar Intrarenal RAS is increased in diabetes and plays a key role in development of diabetic nephropathy.3.Carey R.M. Siragy H.M. The intrarenal renin–angiotensin system and diabetic nephropathy.Trends Endocrinol Metab. 2003; 14: 274-281Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar,16.Anderson S. Jung F.F. Ingelfinger J.R. Renal renin–angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations.Am J Physiol. 1993; 265: F477-F486PubMed Google Scholar Ang II stimulates TGF-β expression and ECM protein production in mesangial and tubular cells;43.Kagami S. Border W.A. Miller D.E. et al.Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial
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