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

Am J Physiol Renal Physiol. 2005 Feb;288(2):F406-11. doi: 10.1152/ajprenal.00099.2004. Epub 2004 Oct 26.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Apoptosis / physiology*
  • Fas Ligand Protein
  • Humans
  • Inflammation
  • Kidney Tubules / pathology*
  • Male
  • Membrane Glycoproteins / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Ureteral Obstruction / complications*
  • Ureteral Obstruction / pathology
  • Ureteral Obstruction / veterinary


  • FASLG protein, human
  • Fas Ligand Protein
  • Faslg protein, rat
  • Membrane Glycoproteins
  • Tumor Necrosis Factor-alpha