Genistein Reduces Albuminuria by Inhibition of Caveolae-Mediated Endocytosis into Glomerular Endothelial and Epithelial Cells

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Background: We previously reported the intracellular trafficking pathway of glomerular endothelial cells (GEnCs) and epithelial cells (podocytes) through caveolae as the possibility of new etiology of albuminuria. The non-steroidal phytoestrogen belonged to potent soy isoflavone, genistein (Gen) inhibits Src kinase, which plays an important role of internalization of caveolae coated pits into cytoplasm as caveolae endocytosis. In this study, we analyzed the effect of Gen to reduce albuminuria by inhibiting albumin endocytosis through caveolae into GEnCs and podocytes. Methods: After 1 hour pre-treating cells with 50, 100, or 200 μM of Gen, cells were incubated with time course treatment of albumin (15, 30, and 60 min), and then the expression of caveolin-1 (Cav-1), albumin, and p-Src were evaluated by immunofluorescence (IF) and western blots (WB) analysis. It was also analyzed whether 14 days treatment of Gen reduced albuminuria in the streptozotocin induced diabetic nephropathy modeled mice (STZ mice). Results: Albumin and caveolin-1 (Cav-1) expression levels were significantly decreased with dose dependent manner of Gen in IF and WB analysis (Figure). The expression of p-Src was also decreased in WB analysis. In vivo study, though body weight and blood glucoses were not changed, Gen significantly decreased the urinary albumin/creatinine ratio in STZ mice (0.28 to 0.05, p=0.02) in comparison to non-treated STZ mice (0.21 to 0.14, p=0.37). Conclusions: Gen interfered albumin endocytosis through caveolae by suppressing caveolae expression according to inhibit Src kinase and resulted in reduced albuminuria in STZ mice. These results indicated the possibility of Src kinase inhibitor, Gen as the new therapeutic approach to reduce albuminuria in diabetic nephropathy.Gen interfered albumin internalization by the disruption of caveolae in podocytes.Gen interfered albumin internalization by the disruption of caveolae in GEnCs.

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