Signal regulatory protein α protects podocytes through promotion of autophagic activity

High autophagic activity in podocytes, terminally differentiated cells that serve as main components of the kidney filtration barrier, is essential for podocyte survival under various challenges. How podocytes maintain such a high level of autophagy, however, remains unclear. Here we report that signal regulatory protein alpha (SIRP alpha) plays a key role in promoting podocyte autophagy. Unlike other glomerular cells, podocytes strongly expressed SIRP alpha, which was, however, downregulated in patients with focal segmental glomerulosclerosis and mice with experimental nephropathy. Podocyte SIRP alpha levels were inversely correlated with the severity of podocyte injury and proteinuria but positively with autophagy. Compared with WT littermates, Sirpa-deficient mice displayed greater age-related podocyte injury and proteinuria and developed more rapid and severe renal injury in various models of experimental nephropathy. Mechanistically, podocyte SIRP alpha, strongly reduced Akt/GSK-3 beta/beta-caten in signaling, leading to an increase in autophagic activity. Our findings thus demonstrate a critical protective role of SIRP alpha in podocyte survival via maintenance of autophagic activity.