title: Pentoxifylline protects against endotoxin-induced acute renal failure in mice.
abstract: Acute renal failure (ARF) in septic patients drastically increases the mortality to 50-80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-alpha and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-alpha and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 +/- 6.6 vs. 50.2 +/- 6.6 microl/min, P < 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-alpha (1.00 +/- 0.55 vs. 7.02 +/- 2.40 pg/ml, P < 0.05) and serum IL-1beta (31.3 +/- 3.6 vs. 53.3 +/- 5.9 pg/ml, P < 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 +/- 18.0 vs. 44.5 +/- 16.2 microl/min, P < 0.05) and renal blood flow (0.86 +/- 0.08 vs. 0.59 +/- 0.05 ml/min, P < 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 +/- 5.8 vs. 178.0 +/- 7.6 mmHg.ml(-1).min(-1), P < 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-alpha, IL-1beta, and NO as well as a decrease in renal iNOS and ICAM-1.
authors.affiliation: Dept. of Medicine, Univ. of Colorado Health Sciences Center, 4200 East 9th Ave. Box C-281, Denver, CO 80262, USA. robert.schrier@uchsc.edu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Einath
authors.initials: E
authors.lastname: Zolty
authors.forename: Sandor
authors.initials: S
authors.lastname: Falk
authors.forename: Veena
authors.initials: V
authors.lastname: Basava
authors.forename: Leonid
authors.initials: L
authors.lastname: Reznikov
authors.forename: Robert
authors.initials: R
authors.lastname: Schrier
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology; D000527:Alprostadil / Q000031:analogs & derivatives / Q000652:urine; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D019446:Endotoxemia / Q000150:complications*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000097:blood; D007672:Kidney Cortex / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010431:Pentoxifylline / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C090509:Icam1 protein, mouse; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; C022950:6-ketoprostaglandin E1; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D000527:Alprostadil; D006152:Cyclic GMP; D010431:Pentoxifylline