ROLE OF ENDOTHELIUM IN GLOMERULAR DYSFUNCTION

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Previous investigations of acute renal failure have described impairment in regulation of vasomotor tone within the renal circulation, ranging from persistent vasoconstriction to abnormalities in the vascular response to a number of vasodilators and vasoconstrictors. In large part these observations remain without further explanatory mechanisms. Of interest in this regard is the explosion of new information indicating that endothelial cells elaborate powerful vasodilating (endothelium-derived relaxation factor, EDRF) and vasoconstricting (endothelin) substances which can regulate local vascular tone, regional blood flow and, in the kidney, the potential to modulate the process of glomerular filtration. Preliminary data collected thus far, support important roles for both EDRF and endothelin in modulating the renal circulation and GFR. The studies will be performed in Munich-Wistar rats with renal injury secondary to ischemia/reperfusion, exposure to endotoxin and activated polymorphonuclear leukocytes. The proposed projects include a newly developed technique which allows experimental manipulations of portions of a kidney: infusion of a branch of the main renal artery (endothelin, endothelin antibody, endotoxin etc). Micropuncture techniques can compare hemodynamics and morphological techniques can compare the structural changes in manipulated and non manipulated glomeruli/vasculature within that kidney. The specific aims include: 1) Physiologic assessment of the contribution of endothelial cells to abnormal renal hemodynamics in several forms of acute renal failure and the role of reactive oxygen species in these phenomenon. 2) Morphological assessment within the renal microcirculation to exogenous/endogenous endothelin. 3) Assessment of modulation by endothelium-derived substances by measuring biochemical markers in normal and injured kidneys, glomeruli and mesangial cells. 4) Assessment of endothelin in plasma and other physiologic fluids in conditions having injured endothelial cells. 5) Characterization of glomerular endothelin receptors in injured kidneys.