Vitamin D receptor attenuates renal fibrosis by suppressing the renin-angiotensin system.
Analogs of vitamin D attenuate renal injury in several models of kidney disease, but the mechanism underlying this renoprotective effect is unknown. To address the role of the vitamin D receptor (VDR) in renal fibrogenesis, we subjected VDR-null mice to unilateral ureteral obstruction for 7 days. Compared with wild-type mice, VDR-null mice developed more severe renal damage in the obstructed kidney, with marked tubular atrophy and interstitial fibrosis. Significant induction of extracellular matrix proteins (fibronectin and collagen I), profibrogenic and proinflammatory factors (TGF-beta, connective tissue growth factor, and monocyte chemoattractant protein 1), and epithelial-to-mesenchymal transition accompanied this histologic damage. Because VDR ablation activates the renin-angiotensin system and leads to accumulation of angiotensin II (AngII) in the kidney, we assessed whether elevated AngII in the VDR-null kidney promotes injury. Treatment with the angiotensin type 1 antagonist losartan eliminated the difference in obstruction-induced interstitial fibrosis between wild-type and VDR-null mice, suggesting that AngII contributes to the enhanced renal fibrosis observed in obstructed VDR-null kidneys. Taken together, these results suggest that the VDR attenuates obstructive renal injury at least in part by suppressing the renin-angiotensin system.
Zhang
Yan
Y
Department of Medicine, University of Chicago, 900 E. 57th Street, KCBD, Mailbox 9, Chicago, IL 60637, USA.
Kong
Juan
J
Deb
Dilip K
DK
Chang
Anthony
A
Li
Yan Chun
YC
D000803:Angiotensin I / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology; D024042:Collagen Type I / Q000502:physiology; D055513:Connective Tissue Growth Factor / Q000502:physiology; D004195:Disease Models, Animal; D005353:Fibronectins / Q000502:physiology; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000235:genetics / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
C526318:CCN2 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D005353:Fibronectins; D018167:Receptors, Calcitriol; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D000803:Angiotensin I; D019808:Losartan