Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
"L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
JCI Insight. 2020 Mar 12;5(5):131849. doi: 10.1172/jci.insight.131849.
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.
补体系统在糖尿病肾病（DN）患者中的肾脏激活已被描述，尽管其病理相关性仍不明确。在这里，我们研究了肾小球 C3a 是否由不受控制的补体激活产生，从而导致 2 型糖尿病小鼠的足细胞损伤，导致蛋白尿和肾脏损伤。BTBR ob/ob 小鼠表现出足细胞丢失、白蛋白尿和肾小球损伤，伴有 C3 沉积和 C3a 和 C3a 受体（C3aR）水平增加。还观察到肾小球层粘连蛋白和 α-辅肌动蛋白 4 的表达减少，以及整合素连接激酶的诱导。用 C3aR 拮抗剂治疗 DN 小鼠可增强足细胞密度并维持其表型，从而限制蛋白尿和肾小球损伤。在机制上，超微结构和功能线粒体改变伴随着抗氧化超氧化物歧化酶 2（SOD2）的下调和蛋白质氧化增加，发生在足细胞中，并通过 C3aR 阻断得到纠正。在培养的足细胞中，C3a 诱导 cAMP 依赖性线粒体片段化。线粒体膜电位、SOD2 表达和能量代谢的改变也响应 C3a 而发生。值得注意的是，C3a 诱导的足细胞迁移被 SS-31 抑制，SS-31 是一种具有线粒体保护作用的肽。这些数据表明，C3a 阻断代表了一种潜在的新型治疗策略，可通过维持线粒体功能来保护 DN 中的足细胞完整性。
