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1 Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2 Department of Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
* To whom correspondence should be addressed. E-mail: prmayeux{at}uams.edu.
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 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 (E. 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 nitric oxide synthase inhibitor L-N6-1- iminoethyl-lysine (L-NIL) and the non-selective 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.
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