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Am J Physiol Renal Physiol 288: F406-F411, 2005. First published October 26, 2004; doi:10.1152/ajprenal.00099.2004
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TNF-{alpha} mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling

R. Misseri,1 D. R. Meldrum,2 C. A. Dinarello,3 P. Dagher,4 K. L. Hile,1 R. C. Rink,1 and K. K. Meldrum1

The Departments of 1Urology, 4Medicine, and 2Surgery, Indiana University, Indianapolis, Indiana; and the 3Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 26 March 2004 ; accepted in final form 20 October 2004

Obstruction of the upper urinary tract induces a progressive loss in renal mass through apoptotic renal cell death. Although TNF-{alpha} has been implicated in ischemia-reperfusion-induced apoptotic renal cell death, its role in obstructive renal cell apoptosis remains unknown. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Twenty-four hours before surgery and every 84 h thereafter, rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1). The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were subsequently analyzed for TNF-{alpha} (ELISA, RT-PCR), Fas ligand (RT-PCR), apoptosis (TUNEL, ELISA), and caspase 8 and 3 activity (Western blot). Renal obstruction induced increased tissue TNF-{alpha} and Fas ligand mRNA levels, TNF-{alpha} protein production, apoptotic renal tubular cell death, and elevated caspase 8 and 3 activity, whereas treatment with PEG-sTNFR1 significantly reduced obstruction-induced TNF-{alpha} production, renal tubular cell apoptosis, and caspase activity. PEG-sTNFR1 did not significantly alter Fas ligand expression. These results demonstrate that TNF-{alpha} mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling and identify TNF-{alpha} neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

inflammation; tumor necrosis factor receptor 1; kidney; cytokine


Address for reprint requests and other correspondence: K. K. Meldrum, Riley Hospital for Children, 702 Barnhill Drive, Suite 4230, Indianapolis, IN 46202 (E-mail: kmeldrum{at}iupui.edu)




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