C3a Mediates Epithelial-to-Mesenchymal Transition in Proteinuric Nephropathy

Abstract

Tubulointerstitial inflammation and progressive fibrosis are common pathways that lead to kidney failure in proteinuric nephropathies. Activation of the complement system has been implicated in the development of tubulointerstitial injury in clinical and animal studies, but the mechanism by which complement induces kidney injury is not fully understood. Here, we studied the effect of complement on the phenotype of tubular epithelial cells. Tubular epithelial cells exposed to serum proteins adopted phenotypic and functional characteristics of mesenchymal cells. Expression of E-cadherin protein decreased and expression of both ␣-smooth muscle actin protein and collagen I mRNA increased. Exposure of the cells to the complement anaphylotoxin C3a induced similar features. Treating with a C3a receptor (C3aR) antagonist prevented both C3a-and serum-induced epithelial-to-mesenchymal transition. In the adriamycin-induced proteinuria model, C3aR-deficient mice demonstrated less injury, preserved renal function, and improved survival compared with wild-type mice. Furthermore, the kidneys of C3aR-deficient mice had significantly less interstitial collagen I and ␣-smooth muscle actin. In summary, the complement anaphylotoxin C3a is an important mediator of glomerular and tubulointerstitial injury and can induce tubular epithelial-to-mesenchymal transition.

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

“…However, although the pharmacology of SB290157 may be controversial, the conclusion drawn by the investigators could be reinterpreted to take into account the acute "antineutrophil" effects of C3aR that were discovered recently (32). It is uncontroversial that, at least at the level of the nephron, C3aR is involved in the pathogenesis of renal disease, including the induction of metaplasia in nephron epithelial cells central to the disease (65,66). These actions appear synergistic to the role of C5aR1 at the tissue level, but they may be redundant in the presence of elevated C5a concentrations, which is a more potent proinflammatory mediator than C3a, at the receptor level.…”

Cancer and the Complement Cascade

“…E-cadherins create a widespread signaling network capable of relaying antiproliferative messages, thus serving an important tumor-suppressor role (100). Tubulointerstitial damage in proteinuric nephropathy provides evidence of complement-mediated alterations in E-cadherin; more specifically, researchers discovered that C3a/C3aR binding partially induces EMT through decreased expression of E-cadherin protein (109). Indirect evidence of complement-directed loss of E-cadherin function is provided by evidence that C5 induces IGF expression (75).…”

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

“…C3a is a powerful proinflammatory agent that recruits immune cells to sites of infection (chemotaxis) and induces immune cells to secrete bactericidal agents (via degranulation) as well as inflammatory cytokines 13,14 . Overexpression of C3a/C3aR or sustained activation of its receptor can lead to inflammatory diseases, including allergies 10 , asthma 15 , arthritis 16 , sepsis 17 , lupus 18 , diabetes 19 , psoriasis 20 , nephropathy 21 , ischaemia-reperfusion injury 22 , obesity, and metabolic and cardiovascular dysfunction 23 . C3a also reportedly has antimicrobial 24 and antifungal 25 activities.…”