title: TNF-alpha mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling.
abstract: 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.
authors.affiliation: Department of Urology, Indiana University, Indianapolis, Indiana, USA.
authors.forename: R
authors.initials: R
authors.lastname: Misseri
authors.forename: D R
authors.initials: DR
authors.lastname: Meldrum
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: P
authors.initials: P
authors.lastname: Dagher
authors.forename: K L
authors.initials: KL
authors.lastname: Hile
authors.forename: R C
authors.initials: RC
authors.lastname: Rink
authors.forename: K K
authors.initials: KK
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D053222:Fas Ligand Protein; D006801:Humans; D007249:Inflammation; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014517:Ureteral Obstruction / Q000150:complications* / Q000473:pathology / Q000662:veterinary
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha