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Distinct Functions of Activated Protein C Differentially Attenuate Acute Kidney Injury

Akanksha Gupta^*, Bruce Gerlitz^*, Mark A. Richardson^*, Christopher Bull, David T. Berg^*, Samreen Syed, Elizabeth J. Galbreath, Barbara A. Swanson, Bryan E. Jones^* and Brian W. Grinnell^*

^* Biotechnology Discovery Research, Integrative Biology, and Pathology, Lilly Research Laboratories, Indianapolis, Indiana; and Applied Molecular Evolution, San Diego, California

Correspondence: Brian W. Grinnell, Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0444. Phone: 317-276-2293; Fax: 317-277-2934; E-mail: bgrinnell{at}lilly.com

Received for publication March 14, 2008. Accepted for publication August 28, 2008.

Administration of activated protein C (APC) protects from renal dysfunction, but the underlying mechanism is unknown. APC exerts both antithrombotic and cytoprotective properties, the latter via modulation of protease-activated receptor-1 (PAR-1) signaling. We generated APC variants to study the relative importance of the two functions of APC in a model of LPS-induced renal microvascular dysfunction. Compared with wild-type APC, the K193E variant exhibited impaired anticoagulant activity but retained the ability to mediate PAR-1-dependent signaling. In contrast, the L8W variant retained anticoagulant activity but lost its ability to modulate PAR-1. By administering wild-type APC or these mutants in a rat model of LPS-induced injury, we found that the PAR-1 agonism, but not the anticoagulant function of APC, reversed LPS-induced systemic hypotension. In contrast, both functions of APC played a role in reversing LPS-induced decreases in renal blood flow and volume, although the effects on PAR-1-dependent signaling were more potent. Regarding potential mechanisms for these findings, APC-mediated PAR-1 agonism suppressed LPS-induced increases in the vasoactive peptide adrenomedullin and infiltration of iNOS-positive leukocytes into renal tissue. However, the anticoagulant function of APC was responsible for suppressing LPS-induced stimulation of the proinflammatory mediators ACE-1, IL-6, and IL-18, perhaps accounting for its ability to modulate renal hemodynamics. Both variants reduced active caspase-3 and abrogated LPS-induced renal dysfunction and pathology. We conclude that although PAR-1 agonism is solely responsible for APC-mediated improvement in systemic hemodynamics, both functions of APC play distinct roles in attenuating the response to injury in the kidney.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673