Sulforaphane attenuation of experimental diabetic nephropathy involves GSK-3 beta/Fyn/Nrf2 signaling pathway

Sulforaphane (SFN), the bioactive component of cruciferous vegetables, is a potent indirect antioxidant Oxidative stress and activation of glycogen synthase kinase 3beta (GSK3 beta) are two major contributors to the pathogenesis of diabetic nephropathy (DN). Here, we investigated whether and how SFN affected GSK3 beta in experimental models of DN in vivo and in vitro. SFN treatment obviously prevented the increase in urine albumin excretion, matrix expansion, transforming growth factor-beta 1 expression, fibronectin and type IV collagen deposition in the diabetic kidney. Simultaneously, the level of 8-oxo-deoxyguanosine, an indicator of oxidative damage, was markedly lowered in SFN-treated diabetic rats, together with a significant reduction in activity of the GSK-3 beta/Fyn axis and an evident activation of Nrf2 signaling. Similarly, antifibrotic effects of SFN, parallel to enhanced inhibitory Ser9-phosphorylation of GSK3 beta and Fyn/Nrf2 nuclear export/import, were observed in the cultured rat mesangial cells (RMC) exposed to high glucose. The salutary effects of SFN on high-glucose-stimulated RMC were abolished by overexpression of GSK3 beta while being rescued by lithium chloride, a well-known GSK3 beta inhibitor. Taken together, our findings suggested that SFN ameliorated experimental diabetic nephropathy, at least in part, via GSK3 beta/Fyn/Nrf2 signaling pathway. (C) 2015 Elsevier Inc. All rights reserved.