DESCRIPTION (adapted from the application) Liver disease induces a spectrum of renal abnormalities. Early on there is redistribution of intrarenal RBF; that is there is cortical vasoconstriction with shunting of RBF towards the juxtamedullary nephrons, which may contribute to enhanced sodium and water retention. However, the mechanisms leading to these alterations are not clear. Recent studies have described a new family of prostaglandin-like compounds, F2-isoprostanes, that are formed in vivo by free-radical catalyzed peroxidation of arachidonic acid. These compounds are markers of oxidant injury, possess biological activity and are markedly elevated in liver disease. Yet their role in the associated renal dysfunction is poorly understood. We hypothesize that elevated oxidative stress in liver disease increases F2-isoprostanes, which in turn contribute to the altered renal hemodynamics. In our first aim, we examine whether oxidative stress via F2-isoprostanes contributes to the redistribution of intrarenal RBF induced by chronic bile duct ligation (c-BDL). The rationale for this aim is that c-BDL increases oxidative stress and causes redistribution of RBF. Thus, using micro-CT technology, we will examine whether by acutely or chronically blocking oxidative stress or the F2-isoprostanes receptor reverses or prevents the redistribution of RBF. The next aims assess the direct actions of isoprostanes, and what role oxidative stress via isoprostanes plays in the renal vascular abnormalities of the c-BDL rats. For this, we will study vascular reactivity in isolated microperfused afferent arterioles dissected from the superficial and juxtamedullary cortex (s-Af-Arts and jm-Af-Arts respectively), of control and c-BDL rats. In aim #2 we test the hypothesis that s-Af-Arts are more sensitive than jm-Af-Arts isoprostane-induced vasoconstriction, which thus may explain why renal medullary perfusion is preserved despite marked cortical hypoperfusion. In aim #3 we test the hypothesis that vascular reactivity of s-Af-Art but not jm-Af-Arts is enhanced in c-BDL compared to controls (contributing to the above-mentioned redistribution of RBF). If we find that Af-Art reactivity is altered, we will test the hypothesis that the enhanced reactivity is due to oxidative stress via increased isoprostanes by determining whether treatment with antioxidants or isoprostane antagonists improves the vascular parameters. Finally, because bile acids are very elevated in c-BDL, and can themselves promote oxidative stress, aim #4 tests the hypothesis that the elevated bile acids themselves contribute to the enhanced Af-Art reactivity via their pro-oxidant actions. We will examine the effects that bile acids have on s- and jm-Af-Art diameter, and reactivity (as in aim #2). This information will complement that obtained in aim #2 (where the exposure to bile acids is chronic in vivo rather than acute in vitro). Our proposed application therefore characterizes the renal vascular actions of oxidative stress and isoprostanes, and evaluates their role in the c-BDL rats.

K08DK002943

2001-05-01

2006-01-31