Sepsis and septic shock are associated with a high incidence of acute renal failure (ARF). Moreover, the combination of sepsis and ARF leads to a very high mortality ranging from 50-80%. Endotoxemia during sepsis is associated with systemic arterial vasodilation secondary to 1) a large increase in vasodilating nitric oxide (NO) generated by the inducible isoform of nitric oxide synthase (iNOS) and 2) reduced plasma volume due to increased endothelin (ET- 1)-induced capillary leak. The resultant relative underfilling of the arterial circulation initiates compensatory vasoconstrictors of the sympathetic nervous system and renin angiotensin system which maintain mean arterial pressure at the expense of renal vasoconstriction, an important predisposing factor to ARF. ET-1 may also exert a vasoconstrictor effect systemically and on the kidney.
In Specific Aim 1, the effect on renal function of specific iNOS versus non-specific NOS inhibition during endotoxemia will be studied; the role of eNOS will be examined in eNOS knockout mice.
In Specific Aim 2, the role of ET- 1 will be examined by assessment of renal function and capillary leak during early endotoxemia in ET-1 knockout mice and mice treated with an ET receptor antagonist.
Specific Aim 3 will study the role of the interaction of the NO and ET-1 systems by examining the result of non-specific versus specific iNOS inhibition on ET-1 gene and protein expression. Understanding the early vasoactive events which cause ARF during endotoxemia would be a major medical advance, thereby allowing the development of pathogenetic-based interventions.
