Nitric oxide (NO) regulates arterial blood pressure and kidney function by influencing systemic vascular resistance and fluid and electrolyte homeostasis. Despite the large amount of research on this subject, the factors important in the regulation of NO production in the kidney have not been clearly defined. Previous work from our laboratory demonstrated the importance of L-Arginine (L-Arg) uptake mechanisms in renal epithelial cells. Exciting new results from our laboratory indicate that cellular uptake of L-Arg, the substrate for NO synthase, is also a critical modulator of NO production in renal vascular endothelial cells. L-Arg uptake is therefore also an important regulator of renal vascular resistance with resulting effects on kidney excretory function. New data will be presented indicating that mechanisms of L-Arg transport have important effects on NO production and NO-dependent function in the renal vasculature. Using these novel data as a rationale and a unique integrative experimental approach, we will define the role of the L-Arg transporters in the regulation of renal vascular function in vitro and in vivo to provide an understanding of the importance of this physiological regulator of NO production. Experiments will test the General Hypothesis that cellular L-arginine uptake by y+ and y+L transporters in endothelial cells of the renal vasculature mediates the production of NO by altering the availability of NOS substrate in vivo and plays a critical role in the regulation of renal function as well as fluid and electrolyte homeostasis. This hypothesis will be addressed in three specific aims.
Specific Aim 1 will utilize unique cellular and molecular techniques to identify the L-Arg uptake mechanisms and transporters in renal blood vessels.
Aim 2 will employ novel methodology to determine the functional importance of these transporters in the renal vasculature on NO production and NO-dependent function both in vitro and in vivo in normal and diseased animals. Experiments in Aim 3 will then make use of genetically manipulated mice to determine which NOS isoform is affected by cellular L-Arg uptake mechanisms. This novel combination of experimental methods will be used to elucidate the important role of L-Arg transport in the regulation of renal vascular resistance and kidney function. The results of these studies may provide important insight into the causes of hypertension and vascular-related complications that are a leading cause of death and morbidity in the US.
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