TY - JOUR AU - Morigi, Marina AU - Perico, Luca AU - Corna, Daniela AU - Locatelli, Monica AU - Cassis, Paola AU - Carminati, Claudia Elisa AU - Bolognini, Silvia AU - Zoja, Carlamaria AU - Remuzzi, Giuseppe AU - Benigni, Ariela AU - Buelli, Simona T1 - C3a receptor blockade protects podocytes from injury in diabetic nephropathy PY - 2020/03/12/ AB - Renal activation of the complement system has been described in patients with diabetic nephropathy (DN), although its pathological relevance is still ill-defined. Here, we studied whether glomerular C3a, generated by uncontrolled complement activation, promotes podocyte damage, leading to proteinuria and renal injury in mice with type 2 diabetes. BTBR ob/ob mice exhibited podocyte loss, albuminuria, and glomerular injury accompanied by C3 deposits and increased C3a and C3a receptor (C3aR) levels. Decreased glomerular nephrin and α-actinin4 expression, coupled with integrin-linked kinase induction, were also observed. Treatment of DN mice with a C3aR antagonist enhanced podocyte density and preserved their phenotype, limiting proteinuria and glomerular injury. Mechanistically, ultrastructural and functional mitochondrial alterations, accompanied by downregulation of antioxidant superoxide dismutase 2 (SOD2) and increased protein oxidation, occurred in podocytes and were normalized by C3aR blockade. In cultured podocytes, C3a induced cAMP-dependent mitochondrial fragmentation. Alterations of mitochondrial membrane potential, SOD2 expression, and energetic metabolism were also found in response to C3a. Notably, C3a-induced podocyte motility was inhibited by SS-31, a peptide with mitochondrial protective effects. These data indicate that C3a blockade represents a potentially novel therapeutic strategy in DN for preserving podocyte integrity through the maintenance of mitochondrial functions. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.131849 VL - 5 IS - 5 UR - https://doi.org/10.1172/jci.insight.131849 PB - The American Society for Clinical Investigation ER -