Podocyte dysfunction, one of the major causes of proteinuria, leads to glomerulosclerosis and end stage renal disease, but its underlying mechanism remains poorly understood. Angptl4 has been reported to mediate proteinuria in some types of glomerulonephropathy. However, the underlying molecular mechanism remains unclear. This study aimed to investigate the role of Angptl4 in the pathogenesis of DN. In this study, we found that expression of ANGPTL4 in the kidney cortex was significantly increased in the diabetic mouse. Moreover, we demonstrated that ANGPTL4 induced podocytes apoptosis and actin cytoskeleton derangement via integrin pathway under high glucose. High glucose increased integrinα3β1 in podocytes. Our results showed ANGPTL4-induced podocytes apoptosis and actin cytoskeleton damage was effectively attenuated by blocking ANGPTL4 and integrin α3β1 by neutralizing antibody in vitro. Furthermore, we demonstrated that the effect of ANGPTL4 on podocyte damage is due to increased podocyte-secreted hyposialylated ANGPTL4 under high glucose, and these effects were effectively attenuated by conversion of hyposialylated ANGPTL4 to its sialylated form with ManNAc in both vivo and vitro. Taken together, these results indicate that targeting Angptl4 related signaling may represent a novel therapeutic strategy for proteinuric kidney diseases.


H. Chen: None. K. Guo: None. P. Pan: None.

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