Renoprotective role of the vitamin D receptor 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-beta (TGF-beta), 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-beta in mesangial and juxtaglomerular cells. Our study suggests that receptor-mediated vitamin D actions are renoprotective in diabetic nephropathy.
Zhang
Z
Z
Division of Biological Sciences, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
Sun
L
L
Wang
Y
Y
Ning
G
G
Minto
A W
AW
Kong
J
J
Quigg
R J
RJ
Li
Y C
YC
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000517:prevention & control*; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000502:physiology*; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000235:genetics; D014807:Vitamin D / Q000502:physiology
C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D014807:Vitamin D; D013311:Streptozocin; D002117:Calcitriol