Phospho-GSK-3β is involved in the high-glucose-mediated lipid deposition in renal tubular cells in diabetes.

The phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway mediates the high-glucose-induced lipid accumulation in the renal tubular cells in diabetes. Studies have revealed that the downstream target genes of phospho-Akt, BCL2-associated death promoter (Bad) and glycogen synthase kinase-3β (GSK-3β) are associated with lipid accumulation in hepatic cells and preadipocytes. In the present study, it was revealed that the phospho-Akt, phospho-Bad, phosphor-GSK-3β contents and lipogenesis were increased in the renal tubular cells of diabetic rats. However, in high-glucose-treated human renal tubular cells, only the phospho-GSK-3β content increased without an alteration in the phospho-Bad content, which could be reversed by treatment with a short hairpin RNA vector aimed at Akt. Inhibiting GSK-3β activity using TWS119 increased the sterol regulatory element binding protein-1 (SREBP-1) content and lipogenesis in renal tubular cells. Furthermore, the exogenous expression of wild-type GSK-3β enhanced the level of phospho-GSK-3β in high-glucose-stimulated renal tubular cells, followed by increased SREBP-1 expression and lipogenesis. Moreover, exogenous expression of mutant GSK-3β (via vector S9A) prevented the increase in SREBP-1 expression and cellular lipogenesis by decreasing the phospho-GSK-3β content and increasing the GSK-3β activity in high-glucose-treated cells. These data suggested that phospho-GSK-3β is involved in the high-glucose-mediated increase of SREBP-1 expression and triglyceride content in renal tubular cells in diabetes.