Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: Role of nitric oxide and caspases

Manish M. Tiwari, Robert W. Brock, Judit K. Megyesi, Gur P. Kaushal, Philip R. Mayeux

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

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 C57BLV6 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-N6-1-iminoethyl-lysine (L-NDL) 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.

Original languageEnglish (US)
Pages (from-to)F1324-F1332
JournalAmerican Journal of Physiology - Renal Physiology
Volume289
Issue number6 58-6
DOIs
StatePublished - Dec 1 2005

Keywords

  • Acute renal failure
  • Apoptosis
  • Benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone
  • Inducible nitric oxide synthase
  • Intravital video-microscopy
  • L-N -1-iminoethyl-lysine

ASJC Scopus subject areas

  • Physiology
  • Urology

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