Distinct roles for basal and induced COX-2 in podocyte injury.

Cheng H, Fan X, Guan Y, Moeckel GW, Zent R, Harris RC
J Am Soc Nephrol. 2009 20 (9): 1953-62

PMID: 19643929 · PMCID: PMC2736764 · DOI:10.1681/ASN.2009010039

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.

MeSH Terms (21)

Albuminuria Animals Antibiotics, Antineoplastic Apoptosis Cell Adhesion Cell Line, Transformed Cell Survival Cyclooxygenase 2 Dinoprostone Doxorubicin Glomerulonephritis Male Mice Mice, Inbred Strains Mice, Transgenic Podocytes Puromycin Receptors, Prostaglandin E Receptors, Thromboxane RNA, Messenger Thromboxanes

Connections (5)

This publication is referenced by other Labnodes entities: