Pilot--Mechanism of End-organ Damage in eNOS Deficiency

North Carolina Central University, Durham NC

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Abstract

The overall goal of the research program is to understand the mechanism(s) of end-organ damage, particularly end-stage renal disease (ESRD). This research problem is relevant to the clinical problem of the increased incidence of target organ damage associated with hypertension. Although the rate of stroke and heart disease has gradually declined over the last several decades, the rate of ESRD has been steadily increasing. The African American population particularly experiences a disproportionately greater risk for ESRD. We hypothesize that one possible mechanism of ESRD associated with hypertension may be stressed-induced renal ischemia in the presence of impaired NO bioavailability. In support of this goal, preliminary data generated in the applicant's laboratory demonstrate that the physiologic stress of infrequent bouts of exhaustive exercise cause progressive gross histologic renal damage in the moderately hypertensive endothelial NO synthase (eNOS) knockout mouse, but not in the wild type control. It is proposed that physiologic stress such as infrequent exhaustive exercise results in increased renal vasoconstrictor activity and ischemia which in turn lead to increased production of reactive oxygen species and cytokine production in the face of an NO deficiency. Therefore, in an effort to generate preliminary data to support this hypothesis we propose the following Specific Aims. Specific Aim 1 is designed to generate renal vasoconstriction data. Mice will be chronically implanted with both renal blood flow (RBF) and blood pressure probes to measure RBF and blood pressure at rest and during physiologic stress of infrequent running to exhaustion in control and eNOS knockout mice. Renal vascular resistance will be calculated from these values. It is expected that eNOS knockout mice will have a greater and more sustained renal vasoconstriction with subsequent ischemia as compared to normal wild type mice. Specific Aim 2 is designed to generate data showing that ischemia develops in the kidney during the stress of infrequent running to exhaustion. Plasma, urine as well as tissue will be collected for measurement of markers of vascular ischemia. Since it is not certain which markers are best to specifically detect renal ischemia we will measure various vascular ischemia markers in plasma, urine and renal tissue.