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Pentoxifylline protects against endotoxin-induced acute renal failure in mice

Pentoxifylline protects against endotoxin-induced acute renal failure in mice Acute renal failure (ARF) in septic patients drastically increases the mortality to 50–80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-α (TNF-α), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-α and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-α 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 µl/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-α (1.00 ± 0.55 vs. 7.02 ± 2.40 pg/ml, P < 0.05) and serum IL-1 (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 µl/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-α, IL-1 , and NO as well as a decrease in renal iNOS and ICAM-1. sepsis; tumor necrosis factor Address for reprint requests and other correspondence: R. Schrier, Dept. of Medicine, Univ. of Colorado Health Sciences Center, 4200 East 9th Ave. Box C-281, Denver, CO 80262 (e-mail: [email protected] ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Renal Physiology The American Physiological Society

Pentoxifylline protects against endotoxin-induced acute renal failure in mice

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References (49)

Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0363-6127
eISSN
1522-1466
DOI
10.1152/ajprenal.00517.2005
pmid
16985210
Publisher site
See Article on Publisher Site

Abstract

Acute renal failure (ARF) in septic patients drastically increases the mortality to 50–80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-α (TNF-α), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-α and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-α 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 µl/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-α (1.00 ± 0.55 vs. 7.02 ± 2.40 pg/ml, P < 0.05) and serum IL-1 (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 µl/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-α, IL-1 , and NO as well as a decrease in renal iNOS and ICAM-1. sepsis; tumor necrosis factor Address for reprint requests and other correspondence: R. Schrier, Dept. of Medicine, Univ. of Colorado Health Sciences Center, 4200 East 9th Ave. Box C-281, Denver, CO 80262 (e-mail: [email protected] )

Journal

AJP - Renal Physiology – The American Physiological Society

Published: Nov 1, 2006

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