Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: role of nitric oxide and caspases.
Acute renal failure (ARF) is a frequent and serious complication of endotoxemia caused by lipopolysaccharide (LPS) and contributes significantly to mortality. The present studies were undertaken to examine the roles of nitric oxide (NO) and caspase activation on renal peritubular blood flow and apoptosis in a murine model of LPS-induced ARF. Male C57BL/6 mice treated with LPS (Escherichia coli) at a dose of 10 mg/kg developed ARF at 18 h. Renal failure was associated with a significant decrease in peritubular capillary perfusion. Vessels with no flow increased from 7 +/- 3% in the saline group to 30 +/- 4% in the LPS group (P < 0.01). Both the inducible NO synthase inhibitor L-N(6)-1-iminoethyl-lysine (L-NIL) and the nonselective caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (Z-VAD) prevented renal failure and reversed perfusion deficits. Renal failure was also associated with an increase in renal caspase-3 activity and an increase in renal apoptosis. Both L-NIL and Z-VAD prevented these changes. LPS caused an increase in NO production that was blocked by L-NIL but not by Z-VAD. Taken together, these data suggest NO-mediated activation of renal caspases and the resulting disruption in peritubular blood flow are an important mechanism of LPS-induced ARF.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
Manish M
MM
Tiwari
Robert W
RW
Brock
Judit K
JK
Megyesi
Gur P
GP
Kaushal
Philip R
PR
Mayeux
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D007371:Interferon-gamma / Q000097:blood; D007672:Kidney Cortex / Q000098:blood supply / Q000473:pathology; D008070:Lipopolysaccharides; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D012079:Renal Circulation / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D008070:Lipopolysaccharides; C090663:N(6)-(1-iminoethyl)lysine; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D020169:Caspases; D008239:Lysine