Distinct roles for basal and induced COX-2 in podocyte injury.
Authors Cheng H, Fan X, Guan Y, Moeckel GW, Zent R, Harris RC
Submitted By Raymond Harris on 8/11/2010
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2009
Date Published 9/1/2009
Volume : Pages 20 : 1953 - 1962
PubMed Reference 19643929
Abstract Transgenic mice that overexpress cyclooxygenase-2 (COX-2) selectively in
podocytes are more susceptible to glomerular injury by adriamycin and puromycin
(PAN). To investigate the potential roles of COX-2 metabolites, we studied mice
with selective deletion of prostanoid receptors and generated conditionally
immortalized podocyte lines from mice with either COX-2 deletion or
overexpression. Podocytes that overexpressed COX-2 were virtually
indistinguishable from wild-type podocytes but were significantly more sensitive
to PAN-induced injury, produced more prostaglandin E(2) and thromboxane B(2),
and had greater expression of prostaglandin E(2) receptor subtype 4 (EP(4)) and
thromboxane receptor (TP). Treatment of COX-2-overexpressing podocytes with a TP
antagonist reduced apoptosis, but treatment with an EP(4) antagonist did not. In
contrast, podocytes from COX-2-knockout mice exhibited increased apoptosis,
markedly decreased cell adhesion, and prominent stress fibers. In vivo,
selective deletion of podocyte EP(4) did not alter the increased sensitivity to
adriamycin-induced injury observed in mice overexpressing podocyte COX-2. In
contrast, genetic deletion of TP in these mice prevented adriamycin-induced
injury, with attenuated albuminuria and foot process effacement. These results
suggest that basal COX-2 may be important for podocyte survival, but
overexpression of podocyte COX-2 increases susceptibility to podocyte injury,
which is mediated, in part, by activation of the thromboxane receptor.

Investigators with authorship
Raymond HarrisVanderbilt University