A novel role of angiopoietin-like-3 associated with podocyte injury

Background: Angiopoietin-like-3 (ANGPTL3) expression is increased in glomerular podocytes of nephrotic syndrome. We hypothesize whether ANGPTL3 plays an important role in podocyte injury and promoting proteinuria. Methods: Angptl3 +/+ and Angptl3 −/− female mice on B6;129S5 gene background were injected with adriamycin by tail vein at the dose of 25 mg/Kg to produce nephropathy. Proteinuira was measured and podocytes ultrastructure was observed by electron microscopy. The interaction between ANGPTL3 and intergrin β3 was analyzed by CO-IP and confocal immunofluorescence. The relative gene and protein expression were analyzed by RT-PCR and western blot. Results: The deletion of ANGPTL3 tremendously attenuates proteinuria (more than a fivefold decrease in albuminuria) and protects podocytes from injury in a mouse model of adriamycin-induced nephropathy. We further demonstrate that ANGPTL3 interacts with and activates podocyte-expressed integrin β3 and regulate expression of α-actinin-4, which may result in the cytoskeletal rearrangement of podocytes. Additionally, we identify the activation of the ANGPTL3-integrin β3 signaling pathway in patients with nephrotic syndrome. Conclusion: ANGPTL3 might play a crucial role in podocyte injury. Either decreasing ANGPTL3 expression or interfering with the ANGPTL3-integrin β3 interaction might be benefit for podocyte protection and decrease proteinuira.