The overall objective of this continuing application is to prove that an abnormality of a D1 receptor or its regulation in renal proximal tubules causes high blood pressure in genetic hypertension. The abnormality results in defective signal transduction, decreased inhibition of the Na+/H+ exchanger (NHE) and Na+/K+ATPase activity in renal proximal tubules, sodium retention, and hypertension. Therefore: 1. The hypothesis that a D1-like receptor defect cosegregates with high blood pressure will be tested by studying the renal D1-like receptor in an F2 generation of mated Wistar Kyoto (WKY) and spontaneously hypertensive rat (SHR). The natriuretic effect of dopamine and D1 agonists will be studied in vivo; proximal tubular reabsorption will be determined by lithium clearance. Renal proximal tubular D1-like receptor density and affinity, D1A receptor protein expression, coupling to effector enzymes (phospholipase C, adenylyl cyclase) and sodium transporters (NHE, Na+/K+ATPase) will be studied in vitro. Nephron segment specificity will be re-examined in these rats by also studying the medullary thick ascending limbs of Henle, and cortical collecting ducts. Organ specificity will be determined by studying the striatum of the brain where the D1A receptor is expressed in high abundance. Receptor specificity will be determined by studying alpha2-, beta-adrenergic and parathyroid hormone effects; their receptors are found in proximal tubules. 2. The hypothesis that a generalized defect in the D1A receptor produces NaCl-sensitive hypertension will be studied in transgenic mice lacking a functional D1A receptor. 3. The hypothesis that the D1A but not the D1B receptor in the SMR is mistargeted to the surface membrane of renal proximal tubules in SHR will be tested. Further, it will be determined if the mistargeting of the D1A receptor is a cause of its uncoupling from its G-protein-effector enzyme complex. The mechanism of the mistargeting of the receptor will be studied by determining the role of post-translational modification of the receptor protein (phosphorylation, glycosylation, and palmitoylation). These studies should determine if a defect in the D1A receptor causes hypertension in animals. Identification of such a defect should pave the way for the study of the D1 receptor defect in NaCl-sensitive human essential hypertension.
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