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C3a Mediates Epithelial-to-Mesenchymal Transition in Proteinuric Nephropathy

Ziyong Tang^*,, Bao Lu, Ellen Hatch, Steven H. Sacks^* and Neil S. Sheerin

^* King's College London, Department of Nephrology and Transplantation, Guy's Hospital London, London, United Kingdom; Department of Nephrology, Peking University Third Hospital, Beijing, China; Division of Pulmonary Medicine and Ina Sue Perlmutter Laboratory, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts; and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

Correspondence: Dr. Neil Sheerin, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. Phone: 0191-222-7146; Fax: 0191-222-0723; E-mail neil.sheerin{at}ncl.ac.uk

Received for publication April 29, 2008. Accepted for publication November 3, 2008.

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.

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