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

R Misseri1, D R Meldrum, C A Dinarello

  • 1Department of Urology, Indiana University, Indianapolis, Indiana, USA.

American Journal of Physiology. Renal Physiology
|October 28, 2004
PubMed

Insights

Tumor necrosis factor-alpha (TNF-alpha) drives kidney cell death during upper urinary tract obstruction. Neutralizing TNF-alpha with PEG-sTNFR1 therapy significantly reduced apoptosis and protected renal mass.

Area of Science:

  • Nephrology
  • Immunology
  • Cell Biology

Background:

  • Upper urinary tract obstruction causes progressive renal mass loss via apoptosis.
  • The role of Tumor Necrosis Factor-alpha (TNF-alpha) in obstructive nephropathy-induced apoptosis is not well understood.
  • TNF-alpha is implicated in apoptosis following ischemia-reperfusion injury.

Purpose of the Study:

  • To investigate the role of TNF-alpha in renal tubular cell apoptosis induced by upper urinary tract obstruction.
  • To evaluate the therapeutic potential of neutralizing TNF-alpha in obstructive nephropathy.

Main Methods:

  • Male Sprague-Dawley rats underwent unilateral ureteral obstruction or sham surgery.
  • Rats received vehicle or pegylated soluble TNF receptor type 1 (PEG-sTNFR1) pre- and post-surgery.
  • Kidney tissues were analyzed for TNF-alpha, Fas ligand, apoptosis markers, and caspase activity.

Main Results:

  • Renal obstruction increased TNF-alpha production, Fas ligand expression, tubular cell apoptosis, and caspase 8/3 activity.
  • PEG-sTNFR1 treatment significantly decreased TNF-alpha levels, apoptosis, and caspase activity.
  • Fas ligand expression was not significantly altered by PEG-sTNFR1 treatment.

Conclusions:

  • TNF-alpha mediates renal tubular cell apoptosis and proapoptotic signaling during upper urinary tract obstruction.
  • Neutralization of TNF-alpha represents a potential therapeutic strategy for obstructive renal injury.

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