Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 300, Issue 3, Pages F801-F810Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00338.2010
Keywords
diabetes; proteinuria; fatty acid and cholesterol synthesis
Categories
Funding
- Genzyme
- Univ. of Colorado [R25 GM-083333]
- National Institutes of Health (NIH) [ARRA 3R01-AG-026529-03S1, U01-DK-076134, R01-AG-026529]
- Univ. of Colorado Department of Medicine
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Wang XX, Jiang T, Shen Y, Santamaria H, Solis N, Arbeeny C, Levi M. Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism. Am J Physiol Renal Physiol 300: F801-F810, 2011. First published January 5, 2011; doi: 10.1152/ajprenal.00338.2010.-Diet-induced obesity (DIO) and insulin resistance in mice are associated with proteinuria, renal mesangial expansion, accumulation of extracellular matrix proteins, and activation of oxidative stress, proinflammatory cytokines, profibrotic growth factors, and the sterol regulatory element binding proteins, SREBP-1 and SREBP-2, that mediate increases in fatty acid and cholesterol synthesis. The purpose of the present study was to determine whether treatment of DIO mice with the vitamin D receptor (VDR) agonist doxercalciferol (1 alpha-hydroxyvitamin D2) prevents renal disease. Our results indicate that treatment of DIO mice with the VDR agonist decreases proteinuria, podocyte injury, mesangial expansion, and extracellular matrix protein accumulation. The VDR agonist also decreases macrophage infiltration, oxidative stress, proinflammatory cytokines, and profibrotic growth factors. Furthermore, the VDR agonist also prevents the activation of the renin-angiotensin-aldosterone system including the angiotensin II type 1 receptor and the mineralocorticoid receptor. An additional novel finding of our study is that activation of VDR results in decreased accumulation of neutral lipids (triglycerides and cholesterol) and expression of adipophilin in the kidney by decreasing SREBP-1 and SREBP-2 expression and target enzymes that mediate fatty acid and cholesterol synthesis and increasing expression of the farnesoid X receptor. This study therefore demonstrates multiple novel effects of VDR activation in the kidney which prevent renal manifestations of DIO in the kidney.
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