Glycosphingolipid GM3 prevents albuminuria and podocytopathy induced by anti-nephrin antibody.

Podocytopathy, which is characterized by injury to podocytes, frequently causes proteinuria or nephrotic syndrome. There is currently a paucity of effective therapeutic drugs to treat proteinuric kidney disease. Recent research suggests the possibility that glycosphingolipid GM3 maintains podocyte function by acting on various molecules including nephrin, but its mechanism of action remains unknown. Here, various analyses were performed to examine the potential relationship between GM3 and nephrin, and the function of GM3 in podocytes using podocytopathy mice, GM3 synthase gene knockout mice, and nephrin injury cells. Reduced amounts of GM3 and nephrin were observed in podocytopathy mice. Intriguingly, this reduction of GM3 and nephrin, as well as albuminuria, were inhibited by administration of valproic acid. However, when the same experiment was performed using GM3 synthase gene knockout mice, valproic acid administration did not inhibit albuminuria. Equivalent results were obtained in model cells. These findings indicate that GM3 acts with nephrin in a collaborative manner in the cell membrane. Taken together, elevated levels of GM3 stabilize nephrin, which is a key molecule of the slit diaphragm, by enhancing the environment of the cell membrane and preventing albuminuria. This study provides novel insight into new drug discovery, which may offer a new therapy for kidney disease with albuminuria.