Complement C5a Moderates Renal Lipid Metabolism and Fibrosis in Diabetic Nephropathy

Abstract

Background: Complement C5 activation has been implicated in tubulointerstitial injury with increased levels of tubular C5a in renal biopsies from patients with diabetic nephropathy. We investigated whether administration of a C5a inhibitor would confer protection against the progression of diabetic nephropathy in an animal model of type 2 diabetes. Methods: Uninephrectomized diabetic db/db mice were administrated with novel C5a inhibitor, NOX-D21 (10 mg/kg, a kind gift from NOXXON) or an equal volume of saline for a total of 12 weeks. Non-diabetic db/m mice were used as control. Results: In db/db mice, treatment with NOX-D21 for 12 weeks did not affect hyperglycemia, but significantly prevented the increase in serum creatinine and BUN levels. These NOX-D21 treated mice had reduced glomerulosclerosis and tubular damage compared to the vehicle-treated diabetic mice. In addition, blockade of C5 signaling reduced the overexpression of TGF-β1, activation of Akt signaling and interstitial expression of fibronectin and collagen type I in the diabetic kidney. NOX-D21 also ameliorated lipid abnormalities in db/db mice and resulted in significant decrease in serum triglycerides and expression of lipid metabolism-related genes (DAGT1 and SREBP-1) in the diabetic kidney. Conclusion: Our findings suggest a pathogenic role of C5a in diabetic nephropathy, especially in regulating TGF-β-driven renal fibrosis. Inhibition of C5a signaling partially improves renal function and ameliorates dyslipidemia in diabetic animals.