C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease

Background. Endothelial-myofibroblast transition (EndMT) has been implicated in the pathogenesis of diabetic renal fibrosis. In this study, the effect of the complement fragments C3a/C5a and their receptor antagonists C3aRA and C5aRA on EndMT in diabetic kidney disease (DKD) and the possible mechanisms were investigated. Methods. The coexpression of CD31 with alpha-smooth muscle (alpha-SMA), C3a receptor (C3aR) and C5a receptor (C5aR) was detected in human renal biopsy tissue obtained from patients with early and advanced DKD and in normal renal tissues from patients with renal-cell carcinoma. The effects of C3aRA and C5aRA on EndMT and the expression of C3a/C3aR, C5a/C5aR, alpha-SMA, CD31, TGF beta, FN and beta-catenin were examined in a streptozotodn (STZ)-induced rat model of DKD and in human renal glomerular endothelial cells (HRGECs) cultured in high glucose and with C3a/C5a, and DKK1 (a Wnt/beta-catenin inhibitor). Results. Double-labeling of alpha-SMA, C3aR, C5aR and CD31 was detected in the glomerulus of renal tissues obtained from biopsies of patients with DKD. Upregulated expression of alpha-SMA, TGF-beta, FN and beta-catenin and downregulated expression of CD31 were detected in the GECs of diabetic rats. The expression of these proteins was inhibited by treatment with C3aRA/C5aRA. In vitro, C3aRA/C5aRA and DKK1 ameliorated the high glucose-induced EndMT and the subsequent expression of alpha-SMA, TGF beta, FN and beta-catenin in HRGECs. Conclusions. The blockade of C3aR/C5aR and the downstream Wnt/beta-catenin pathway may prevent EndMT and alleviate fibrosis in the glomeruli of individuals with DKD. (C) 2015 Elsevier Inc. All rights reserved.