FBXW7 mediates high glucose-induced SREBP-1 expression in renal tubular cells of diabetic nephropathy under PI3K/Akt pathway regulation

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and lipid metabolism abnormality serves a key role in the pathogenesis of DN. Sterol regulatory element-binding protein 1 (SREBP-1) overexpression mediates aberrant lipid accumulation in renal tubular cells of DN. However, the exact mechanism involved in increased SREBP-1 has not been fully elucidated. The aim of the present study was to explore the mechanism involved in SREBP-1 upregulation. Diabetic mice and high glucose-cultured HKC cells were chosen to detect the expression of FBXW7 and SREBP-1 using immunohistochemistry, western blotting and PCR. The present study demonstrated that F-box and WD repeat domain containing 7 (FBXW7) expression was decreased in renal tubular cells of diabetic mice. Moreover, the co-expression of FBXW7 and SREBP-1 was observed in renal tubular cells, but not in the glomeruli. High glucose-induced the downregulation of FBXW7 expression in in vitro cultured HKC cells, which was accompanied by SREBP-1 upregulation. In addition, overexpression of FBXW7 in HKC cells led to SREBP-1 downregulation. By contrast, knockdown of FBXW7 caused SREBP-1 upregulation in HKC cells. It was found that the PI3K/Akt signaling pathway was activated in high glucose-stimulated HKC cells, and inhibition of PI3K/Akt pathway using LY294002 increased FBXW7 expression and decreased SREBP-1 expression. Taken together, the present results suggested that FBXW7 mediated high glucose-induced SREBP-1 expression in renal tubular cells of DN, under the regulation of the PI3K/Akt signaling pathway.

Automated summary

The study showed that FBXW7 mediated the high glucose-induced upregulation of SREBP-1 expression in renal tubular cells of diabetic nephropathy, under the regulation of the PI3K/Akt signaling pathway. Decreased expression of FBXW7 was found in renal tubular cells of diabetic mice, and in vitro experiments demonstrated that manipulation of FBXW7 levels could affect SREBP-1 expression in HKC cells. Additionally, activation of the PI3K/Akt pathway was linked to decreased FBXW7 expression and increased SREBP-1 expression in high glucose-stimulated HKC cells.