Targeting C3a/C5a receptors inhibits human mesangial cell proliferation and alleviates immunoglobulin A nephropathy in mice

Abstract

Complement activation has a deep pathogenic influence in immunoglobulin (Ig)A nephropathy (IgAN). C3a and C5a, small cleavage fragments generated by complement activation, are key mediators of inflammation. The fragments exert broad proinflammatory effects by binding to specific receptors (C3aR and C5aR, respectively). However, no studies thus far have investigated the effects of C3a, C5a and their receptors on IgAN. We observed that C3aR and C5aR antagonists repressed IgA-induced cell proliferation and interleukin (IL)-6 and monocyte chemotactic protein 1 (MCP-1) production in cultured human mesangial cells (HMCs). Furthermore, an IgAN mouse model induced by Sendai virus infection was employed to investigate the effects of C3aR and C5aR on IgAN in vivo for the first time. Wild-type (WT) and several knock-out mouse strains (C3aR or C5aR ) were immunized intranasally with increasing doses of inactivated virus for 14 weeks and were subjected to two intravenous viral challenges during the time-period indicated. In the Sendai virus-induced IgAN model, C3aR/C5aR-deficient mice had significantly reduced proteinuria, lower renal IgA and C3 deposition, less histological damage and reduced mesangial proliferation compared with WT mice. Both C3aR deficiency and C5aR deficiency, especially C3aR deficiency, inhibited renal tumour necrosis factor (TNF)-α, transforming growth factor (TGF)-β, IL-1β, IL-6 and MCP-1 expression significantly. However, C3aR/C5aR-deficient and WT mice with IgAN did not differ with respect to their blood urea nitrogen (BUN) and serum creatinine levels. Our findings provide further support for the idea that C3aR and C5aR are crucially important in IgAN, and suggest that pharmaceutically targeting C3aR/C5aR may hold promise for the treatment of IgAN.

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

“…It is well-established that genetic silencing or the pharmacologic blockade of the receptors for C3a or C5a results in suppression of the pro-inflammatory/pro-fibrotic molecule, TGF-β, in experimental models of lung fibrosis [4], sepsis [32], hepatic metastases of colon cancer [33] and immunoglobin A nephropathy [34]. …”

High levels of urinary complement proteins are associated with chronic renal damage and proximal tubule dysfunction in immunoglobulin A nephropathy

“…Well‐defined cellular or fibrocellular crescents, but not fibrous crescents, were included in the crescent score: C0 equal to no crescents, C1 equal to crescents in less than one‐fourth of glomeruli, and C2 equal to crescents in over one fourth of glomeruli as described previously . The intensity of staining for C3 was scored as follows: 0, invisible; 1, ambiguous under a low‐power lens and apparent under a high‐power lens; 2, apparent under a low‐power lens and clear under a high‐power lens; 3, clear under a low‐power lens and bright under a high‐power lens …”

“…18,19 The intensity of staining for C3 was scored as follows: 0, invisible; 1, ambiguous under a low-power lens and apparent under a highpower lens; 2, apparent under a low-power lens and clear under a high-power lens; 3, clear under a low-power lens and bright under a high-power lens. 20…”

Pathological significance of C3aR signaling in the tumor cells of clear cell renal cell carcinoma: a clinical observation

“…Previously, activation of C3aR was reported to be able to induce epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells [10], the cells from which ccRCC was believed to derive. Besides, activation of C3aR has been reported to promote proliferation of glomerular mesangial cells [11] and cutaneous squamous cell carcinoma cells [12]. To determine whether C3aR signaling also contributes to EMT and proliferation in ccRCC cells, we further examined the expression of the molecular markers for EMT (E-Cadherin and Vimentin) and cell proliferation (Ki-67) in the tumor specimens from ccRCC patients and associate them with the level of C3aR and C3c.…”