TNF- mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling

Misseri, R., D. R. Meldrum, C. A. Dinarello, P. Dagher, K. L. Hile, R. C. Rink, and K. K. Meldrum. TNFmediates obstructioninduced renal tubular cell apoptosis and proapoptotic signaling. Am J Physiol Renal Physiol 288: F406–F411, 2005. First published October 26, 2004; doi:10.1152/ajprenal.00099.2004.—Obstruction of the upper urinary tract induces a progressive loss in renal mass through apoptotic renal cell death. Although TNFhas 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(ELISA, RT-PCR), Fas ligand (RT-PCR), apoptosis (TUNEL, ELISA), and caspase 8 and 3 activity (Western blot). Renal obstruction induced increased tissue TNFand Fas ligand mRNA levels, TNFprotein production, apoptotic renal tubular cell death, and elevated caspase 8 and 3 activity, whereas treatment with PEG-sTNFR1 significantly reduced obstruction-induced TNFproduction, renal tubular cell apoptosis, and caspase activity. PEG-sTNFR1 did not significantly alter Fas ligand expression. These results demonstrate that TNFmediates obstructioninduced renal tubular cell apoptosis and proapoptotic signaling and identify TNFneutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.