1α,25-dihydroxyvitamin D prevents renal oxidative damage via the PARP1/SIRT1/NOX4 pathway in Zucker diabetic fatty rats.

Diabetic nephropathy (DN) is one of the most important renal complications associated with diabetes and the mechanisms are yet to be fully understood. To date, few studies have shown the anti-oxidant effects of 1α,25-dihydroxyvitamin-D3 (1,25(OH)D) on hyperglycemia-induced renal injury. The aim of the present study was to explore the potential mechanism by which 1,25(OH)D reduced oxidative stress in diabetic rat kidneys. In this study, we established a vitamin D-deficient spontaneous diabetes model: 5-6 weeks of age Zucker diabetic fatty (ZDF) rats were treated with or without 1,25(OH)D for 7 weeks, age-matched Zucker lean (ZL) rats served as control. Results showed that ZDF rats treated with 1,25(OH)D had decreased body mass, food intake, water intake and urine volume. 1,25(OH)D ameliorated urine glucose, blood glucose and abnormal glucose tolerance. Additionally, 1,25(OH)D significantly lowered microalbuminuria (MALB), decreased the glomerular basement membrane (GBM) thickness, and in some degree inhibited glomerular hypertrophy, mesangial expansion and tubular dilatation. Furthermore, 1,25(OH)D attenuated renal oxidative damage, as reflected by the levels of MDA, GSH, 4-HNE, 8-OHdG and ROS production, and notably inhibited PARP1, activated SIRT1 and decreased the expression of NOX4. Of interest, the abovementioned proteins could be involved in the anti-oxidant mechanism of 1,25(OH)D in diabetic rat kidneys. Our study showed that oxidative stress might be a major contributor to DN pathogenesis and uncovered the antioxidant role of 1,25(OH)D in diabetic nephropathy which was associated with the PARP1/SIRT1/NOX4 pathway.