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Published ahead of print on July 30, 2009
J Am Soc Nephrol 20: 1953-1962, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2009010039
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BASIC RESEARCH

Distinct Roles for Basal and Induced COX-2 in Podocyte Injury

Huifang Cheng*, Xiaofeng Fan*, Youfei Guan{dagger}, Gilbert W. Moeckel{ddagger}, Roy Zent* and Raymond C. Harris*

*George M. O'Brien Kidney and Urologic Diseases Center and Division of Nephrology and
{ddagger}Division of Pathology, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and
{dagger}Department of Physiology, Medical School of Beijing University, Beijing, China

Correspondence: Dr. Raymond C. Harris, Division of Nephrology, C3121 MCN, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, TN 37232. Phone: 615-322-2150; Fax: 615-343-2675; E-mail: ray.harris{at}vanderbilt.edu

Received for publication January 13, 2009. Accepted for publication April 30, 2009.

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 E2 and thromboxane B2, and had greater expression of prostaglandin E2 receptor subtype 4 (EP4) and thromboxane receptor (TP). Treatment of COX-2-overexpressing podocytes with a TP antagonist reduced apoptosis, but treatment with an EP4 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 EP4 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.


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