Abstract
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.
Highlights
Diabetic nephropathy (DN) is one of the main complications of diabetes and is considered the single strongest predictor of mortality [1, 2]
Since a number of studies have described a causal link between complement activation and mitochondrial functions in diverse cellular systems [22,23,24], we investigated whether glomerular C3a was instrumental to mitochondrial damage in injured podocytes in DN mice
We demonstrated in BTBR ob/ob mice that (a) increased glomerular staining for C3a and C3a receptor (C3aR), upon C3 activation, were associated with podocyte detachment and albuminuria; (b) C3a inhibition by treatment with a C3aR antagonist limited podocyte phenotypic alterations and loss as well as urinary albumin excretion and glomerular injury; and (c) C3a blockade normalized the ultrastructural and functional mitochondrial abnormalities in the podocytes and decreased oxidative stress
Summary
Diabetic nephropathy (DN) is one of the main complications of diabetes and is considered the single strongest predictor of mortality [1, 2]. Glomerular C3 deposits were observed in kidney biopsies [9], and increased levels of the complement-active fragments Bb, C4d, C3a and C5a, and soluble C5b-9 were detected in the urine of patients with DN, compared with those in diabetics without renal involvement [8]. A tight correlation was demonstrated between urinary C3a levels and the severity of glomerular lesions, suggesting that C3a may have a pathogenic role in DN [8] Congruent with these data, the observation that C3a and its receptor C3aR increased in the glomeruli of diabetic rats and that treatment with a C3aR antagonist partially reduced the endothelial-myofibroblast transition and glomerulosclerotic lesions [10], points to C3a as a crucial trigger of endothelial dysfunction in the progression of DN. Whether the glomerular engagement of the C3a/C3aR axis can occur in the neighboring podocytes, impairing their functional integrity and contributing to the development of proteinuria, has not been addressed in DN
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