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

R. Misseri, D. R. Meldrum, C. A. Dinarello, P. Dagher, K. L. Hile, R. C. Rink, K. K. Meldrum

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

Obstruction of the upper urinary tract induces a progressive loss in renal mass through apoptotic renal cell death. Although TNF-α 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-α (ELISA, RT-PCR), Fas ligand (RT-PCR), apoptosis (TUNEL, ELISA), and caspase 8 and 3 activity (Western blot). Renal obstruction induced increased tissue TNF-α and Fas ligand mRNA levels, TNF-α protein production, apoptotic renal tubular cell death, and elevated caspase 8 and 3 activity, whereas treatment with PEG-sTNFR1 significantly reduced obstruction-induced TNF-α production, renal tubular cell apoptosis, and caspase activity. PEG-sTNFR1 did not significantly alter Fas ligand expression. These results demonstrate that TNF-α mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling and identify TNF-α neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

Original languageEnglish (US)
Pages (from-to)F406-F411
JournalAmerican Journal of Physiology - Renal Physiology
Volume288
Issue number2 57-2
DOIs
StatePublished - Feb 1 2005

Keywords

  • Cytokine
  • Inflammation
  • Kidney
  • Tumor necrosis factor receptor 1

ASJC Scopus subject areas

  • Physiology

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