Distinct functions of activated protein C differentially attenuate acute kidney injury

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 rel...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Society of Nephrology Vol. 20; no. 2; p. 267
Main Authors: Gupta, Akanksha, Gerlitz, Bruce, Richardson, Mark A, Bull, Christopher, Berg, David T, Syed, Samreen, Galbreath, Elizabeth J, Swanson, Barbara A, Jones, Bryan E, Grinnell, Brian W
Format: Journal Article
Language:English
Published: United States 01.02.2009
Subjects:
Animals
Humans
Inflammation
Interleukin-18 - metabolism
Interleukin-6 - metabolism
Kidney - injuries
Kidney - metabolism
Kidney Diseases - metabolism
Lipopolysaccharides - metabolism
Male
Microcirculation
Protein C - metabolism
Protein C - physiology
Rats
Rats, Sprague-Dawley
Receptor, PAR-1 - metabolism
Signal Transduction
ISSN:1533-3450, 1533-3450
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1533-3450
1533-3450
DOI:10.1681/ASN.2008030294