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mediates obstruction-induced renal tubular cell apoptosis and pro-apoptotic signaling
1 Department of Urology, Indiana University Medical Center, Indianapolis, IN, USA
2 Department of Medicine, Indiana University Medical Center, Indianapolis, IN, USA
3 Department of Surgery, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: kmeldrum{at}iupui.edu.
Obstruction of the upper urinary tract induces a progressive loss in renal mass through apoptotic renal cell death. While tumor necrosis factor (TNF-
) 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 (UUO) vs. sham-operation. Twenty-four hours prior to surgery and every 84 hours 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 TNF- and Fas ligand mRNA levels, TNF- protein production, apoptotic renal tubular cell death, and elevated caspase 8 and 3 activity, whereas treatment with PEG-sTNFR1 significantly reduced obstruction-induced TNF- production, renal tubular cell apoptosis, and caspase activity. PEG-sTNFR1 did not significantly alter Fas ligand expression. These results demonstrate that TNF- mediates obstruction-induced renal tubular cell apoptosis and pro-apoptotic signaling, and identify TNF- neutralization as a potential therapeutic option
for the amelioration of obstruction-induced renal injury.
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