Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 289, Issue 6, Pages F1324-F1332Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00124.2005
Keywords
acute renal failure; inducible nitric oxide synthase; intravital videomicroscopy; benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone; L-N(6-)iminoethyl-lysine; apoptosis
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Funding
- NIDDK NIH HHS [DK-58324] Funding Source: Medline
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Disruption of renal peritubular blood flow in lipopolysaccharide- induced renal failure: role of nitric oxide and caspases. Am J Physiol Renal Physiol 289: F1324 - F1332, 2005. First published July 5, 2005;doi:10.1152/ajprenal.00124.2005. - 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.
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