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Nephron Exp Nephrol. 2007;107(3):e87-94. Epub 2007 Sep 21.

Puromycin induces reversible proteinuric injury in transgenic mice expressing cyclooxygenase-2 in podocytes.

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  • 1Division of Nephrology, George M. O'Brien Kidney and Urologic Diseases Center, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tenn 37232, USA.

Abstract

Previous studies from our own group and others have demonstrated that cyclooxygenase-2 (COX-2) inhibitors could reduce proteinuria in some experimental models of progressive renal disease. To investigate a possible role of COX-2 in podocytes during the course of self-limited glomerular injury, we administered puromycin nucleoside (PAN) on day 1 (15 mg/100 g BW) and day 3 (30 mg/100 g BW) to wild-type and transgenic mice with podocyte-specific COX-2 expression driven by a nephrin promoter. An additional group received both PAN and the COX-2-specific inhibitor, SC58236 (6 mg/l in drinking water). There was no significant difference in the albumin (microg)/creatinine (mg) ratio between wild-type (26.3 +/- 4.2, n = 8) and transgenic (28.9 +/- 2.3, n = 8) mice under baseline conditions. PAN induced significant albuminuria only in the transgenic mice with a peak at day 3: 72.1 +/- 8.9 microg/mg creatinine (n = 12, p < 0.05, compared with basal level), which remitted by day 10 (37.4 +/- 4.4 microg/mg, n = 7, p < 0.05, compared with day 3). Electron microscopy demonstrated that PAN caused 56.7 +/- 4.2% foot process effacement in transgenic mice compared with 38.8 +/- 4.1% in wild type at day 3. PAN increased immunoreactive COX-2 in glomeruli from transgenic mice (day 3: 1.47 +/- 0.08 fold; day 10: 1.25 +/- 0.16 fold, n = 5-9, p < 0.05 compared with basal level), which was restricted to podocytes. Real time PCR indicated that endogenous COX-2 mRNA increased (2.6 +/- 0.1 fold of wild-type control at day 3 and 2.2 +/- 0.2 at day 10, n = 4, p < 0.05), while the nephrin-driven COX-2 mRNA was unchanged. Nephrin mRNA and protein expression were decreased by PAN in the transgenic mice. The COX-2-specific inhibitor, SC58236, reduced foot process effacement in transgenic mice administered PAN to 21.7 +/- 5.2% and significantly reduced the albuminuria at day 3 (42.2 +/- 3.8, n = 13, p < 0.05 compared with untreated) without significantly altering COX-2 expression. In summary, in transgenic mice with podocyte COX-2 overexpression, PAN increased albuminuria and induced foot process fusion. Thus, increased COX-2 expression increased podocyte susceptibility to further injury.

Copyright 2007 S. Karger AG, Basel.

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