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C3a Is Required for the Production of CXC Chemokines by Tubular Epithelial Cells after Renal Ishemia/Reperfusion¹

Joshua M. Thurman^2,*, Amanda M. Lenderink^*, Pamela A. Royer^*, Kathrin E. Coleman^*, Jian Zhou, John D. Lambris, Raphael A. Nemenoff^*, Richard J. Quigg and V. Michael Holers^*

^* Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; Department of Medicine, University of Chicago, Chicago, IL 60637; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104

The complement system is one of the major ways by which the body detects injury to self cells, and the alternative pathway of complement is rapidly activated within the tubulointerstitium after renal ischemia/reperfusion (I/R). In the current study, we investigate the hypothesis that recognition of tubular injury by the complement system is a major mechanism by which the systemic inflammatory response is initiated. Gene array analysis of mouse kidney following I/R initially identified MIP-2 (CXCL2) and keratinocyte-derived chemokine (KC or CXCL1) as factors that are produced in a complement-dependent fashion. Using in situ hybridization, we next demonstrated that these factors are expressed in tubular epithelial cells of postischemic kidneys. Mouse proximal tubular epithelial cells (PTECs) in culture were then exposed to an intact alternative pathway and were found to rapidly produce both chemokines. Selective antagonism of the C3a receptor significantly attenuated production of MIP-2 and KC by PTECs, whereas C5a receptor antagonism and prevention of membrane attack complex (MAC) formation did not have a significant effect. Treatment of PTECs with an NF-B inhibitor also prevented full expression of these factors in response to an intact alternative pathway. In summary, alternative pathway activation after renal I/R induces production of MIP-2 and KC by PTECs. This innate immune system thereby recognizes hypoxic injury and triggers a systemic inflammatory response through the generation of C3a and subsequent activation of the NF-B system.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Amgen Junior Faculty Research Support Program (J.M.T.) and National Institutes of Health Grants DK064790 (to J.M.T.), GM069736 (to J.D.L.), DK041873 (to R.J.Q.), and AI31105 (to V.M.H.).

² Address correspondence and reprint requests to Dr. Joshua M. Thurman, University of Colorado Health Sciences Center, Division of Renal Diseases and Hypertension, 4200 E. 9th Avenue, B-115, Denver, CO 80262. E-mail address: Joshua.Thurman{at}uchsc.edu

³ Abbreviations used in this paper: I/R, ischemia/reperfusion; ARF, acute renal failure; KC, keratinocyte-derived chemokine; PTEC, proximal tubular epithelial cell; MAC, membrane attack complex.

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