RENIN, RENAL FUNCTION AND THE ENDOTHELIUM

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We propose to examine the regulatory role of the endothelium in the control of renin release, renal blood flow and renal function. In specific aim 1, we hypothesize that various endothelium-derived factors (EDFs), in response to different hormonal stimuli, either inhibit or stimulate renin release, and that the final regulatory activity of the endothelium represents a balance between these effects. We propose to determine whether inhibition of endothelium-derived relaxing factor (EDRF), endothelium-derived contracting factor(s) (EDCF) and/or PGI2 alters renin release when agonists such as bradykinin (BK) or arachidonic acid (AA) (which stimulate both EDFs and renin release) or acetylcholine (Ach) (which stimulates only EDFs) are used. We will use 3 in vitro preparations (renal cortical slices, isolated glomeruli and a cascade bioassay system composed of endothelium in series with kidney slices). These preparations will be challenged with BK, AA and/or Ach, either alone or combined with inhibitors of EDFs, and renin release will be determined. In specific aim 2 we hypothesize that EDRF helps control renin secretion, renal blood flow (RBF) and renal function during changes in perfusion pressure. We also hypothesize that paracrine hormones such as prostaglandins, angiotensin II (AII) and kinins interact with EDRF to regulate renin secretion and renal function. We will determine in vivo whether EDRF exerts different effects (either within or below the range of RBF autoregulation) upon a) renin secretion, b) renal hemodynamics and c) water and electrolyte excretion. We will block EDRF, PG synthesis, kinins and/or AII during changes in renal perfusion pressure and assess plasma renin activity (PRA), RBF, glomerular filtration rate (GFR), and water and electrolyte excretion. In specific aim 3 we hypothesize that in hypertension there are changes in the relationship between EDRF and renal function due to endothelial dysfunction and increased renal perfusion pressure. We will study renal function in spontaneously hypertensive rats (SHR), Dahl salt sensitive rats using inhibitors of EDRF and EDCF within and below the range of autoregulation, we will also study a possible endothelial component of reversing 2K,lC Goldblatt hypertension. These studies will further our understanding of the role of the endothelium as a regulatory factor in the control of renin release and renal function.