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Vitamin D receptor signaling in podocytes protects against diabetic nephropathy.

Abstract
Vitamin D and its analogs have antiproteinuric activity and podocytes express the vitamin D receptor, but whether vitamin D signaling in podocytes accounts for this renoprotection is unknown. To investigate this question, we used the 2.5 kb podocin promoter to target Flag-tagged human vitamin D receptor (hVDR) to podocytes in DBA/2J mice. After the induction of diabetes with streptozotocin, transgenic mice had less albuminuria than wild-type controls. In transgenic mice, a low dose of the vitamin D analog doxercalciferol prevented albuminuria, markedly attenuated podocyte loss and apoptosis, and reduced glomerular fibrosis, but it had little effect on the progression of diabetic nephropathy in wild-type mice. Moreover, reconstitution of VDR-null mice with the hVDR transgene in podocytes rescued VDR-null mice from severe diabetes-related renal damage. In culture, 1,25-dihydroxyvitamin D suppressed high-glucose-induced apoptosis of podocytes by blocking p38- and ERK-mediated proapoptotic pathways. Taken together, these data provide strong evidence that vitamin D/VDR signaling in podocytes plays a critical role in the protection of the kidney from diabetic injury.
AuthorsYouli Wang, Dilip K Deb, Zhongyi Zhang, Tao Sun, Weicheng Liu, Dosuk Yoon, Juan Kong, Yunzi Chen, Anthony Chang, Yan Chun Li
JournalJournal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 23 Issue 12 Pg. 1977-86 (Dec 2012) ISSN: 1533-3450 [Electronic] United States
PMID23123403 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein
  • Receptors, Calcitriol
Topics
  • Animals
  • Apoptosis
  • Diabetes Mellitus, Experimental (complications, metabolism)
  • Diabetic Nephropathies (genetics, metabolism)
  • Female
  • Humans
  • Hyperglycemia (complications, metabolism)
  • Intracellular Signaling Peptides and Proteins (genetics)
  • Male
  • Membrane Proteins (genetics)
  • Mice
  • Mice, Inbred DBA
  • Mice, Knockout
  • Podocytes (metabolism)
  • Pregnancy
  • Promoter Regions, Genetic
  • Receptors, Calcitriol (metabolism)

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