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Gq-Dependent Signaling Upregulates COX2 in Glomerular Podocytes

Liming Wang^*, Patrick J. Flannery^*, Paul B. Rosenberg, Timothy A. Fields and Robert F. Spurney^*

^* Division of Nephrology, Department of Medicine, Division of Cardiology, and Department of Pathology, Duke University and Durham VA Medical Centers, Durham, North Carolina

Correspondence: Dr. Robert F. Spurney, Box 103015, Duke University Medical Center, Durham, NC 27710. Phone: 919-684-9729; Fax: 919-684-3011; E-mail: spurn002{at}mc.duke.edu

Received for publication January 29, 2008. Accepted for publication May 23, 2008.

Accumulating evidence suggests that upregulation of cyclooxygenase 2 (COX2) in glomerular podocytes promotes podocyte injury. Because Gq signaling activates calcineurin and calcineurin-dependent mechanisms are known to mediate COX2 expression, this study investigated the role of Gq in promoting COX2 expression in podocytes. A constitutively active Gq subunit tagged with the TAT HIV protein sequence was introduced into an immortalized podocyte cell line by protein transduction. This stimulated inositol trisphosphate production, activated an nuclear factor of activated T cells–responsive reporter construct, and enhanced levels of both COX2 mRNA and protein compared with cells treated with a Gq protein lacking the TAT sequence. Induction of COX2 was associated with increased prostaglandin E₂ production and podocyte death, both of which were attenuated by selective COX2 inhibition. In vivo, levels of COX2 mRNA and protein were significantly enhanced in podocytes from transgenic mice that expressed podocyte-targeted constitutively active Gq compared with nontransgenic littermates. These data suggest that Gq-dependent signaling cascades stimulate calcineurin and, in turn, upregulate COX2 mRNA and protein, increase eicosanoid production, and cause podocyte injury.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673