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Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury

Neil S. Sheerin^*,,1, Paul Risley^*, Katsu Abe, Ziyong Tang^*,, Wilson Wong^*, Tao Lin^* and Steven H. Sacks^*

^* King’s College London, Department of Nephrology and Transplantation, Guy’s Hospital, London, UK;

School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, UK;

Division of Nephrology, Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan; and

Department of Nephrology, Peking University Third Hospital, Beijing, China

¹Correspondence: School of Clinical Medical Sciences, 4th Fl., William Leech Bldg., The Medical School, Framlington Pl., Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. E-mail: neil.sheerin{at}ncl.ac.uk

Increased exposure of the tubular epithelium to filtered protein is a proposed mechanism of progressive renal failure associated with glomerular disease, but how this protein overload translates into tubular damage remains unclear. We have examined a model of adriamycin-induced proteinuria to determine the effect of locally synthesized C3, the central proinflammatory protein of the complement cascade. C3–/– kidney isografts placed in wild-type C3+/+ mice were protected from proteinuria-associated complement activation, tubular damage, and progressive renal failure despite the presence of abundant circulating C3. The quantity of urinary protein was unaffected by the absence of C3, and thus the influence of C3 was not explained by alteration in the filtered protein load. These results suggest that local synthesis of complement from renal epithelial cells is a critical mediator of tubular damage in proteinuria-associated renal disease. Our results concur with previous findings of increased synthesis of C3 in human tubular epithelium exposed to high concentrations of protein in vitro. Because progressive renal damage in humans associates with proteinuria regardless of cause, our findings have implications for the pathogenesis and treatment of renal failure from many common causes, immunological and nonimmunological.—Sheerin, N. S., Risley, P., Abe, K., Tang, Z., Wong, W., Lin, T., Sacks, S. H. Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury.

Key Words: proteinuria • renal failure • innate immunity