There is substantial evidence for dysfunction of D1-1 ike receptors in hypertension but the precise D1-like receptor involved remains to be determined. One reason is the lack of D1-like receptor ligands selective to either of the D1-like receptor subtype, D1R or D5R This limitation has been overcome by the selective deletion of the D1R and D5R gene in mice: disruption of either receptor gene increases blood pressure and produces hypertension. Data obtained in previous funding period showed that D5-/- mice are hypertensive caused, in part, by activation of sympathetic nervous system and increased oxidative stress. Dopamine and angiotensin II receptors regulate each other and interact to regulate renal function but it is not known which D1-like receptor, D1R or D5R, regulates AT1R action. In renal proximal tubule cells, 75% of D1-like receptor function is afforded by D1R while only 25% is due to D5R. However, D1-like receptor inhibition of renal Na+K+ATPase activity (which is inhibited, in part, by cAMP/PKA) is abrogated and blood pressure is increased in D5-/- mice, in spite of an intact D1R gene. Because renal AT1R protein is increased in D5-/- mice, the impairment of D1R action may be due to increased AT1R expression. This in turn causes salt sensitive hypertension. Indeed, the hypertension of D5-/- is aggravated by increased NaCI intake and AT1R blockade normalizes blood pressure of D5-/- mice. In renal proximal tubule cells, D5R but not D1R decreases AT1R protein that cannot be explained by a decrease in transcription or translation. The D5R is constitutively ubiquitinated and 05R stimulation increases ubiquitination of AT1R. Blockade of proteasomes prevents the D5R-mediated decrease in AT1R protein expression. These data are corroborated in HEK-293 cells expressing D5R and AT1R. Therefore, the increase in AT1R protein in D5-/- mice may be caused may be caused by the failure of D5R to down-regulate AT1 R. It is hypothesized that D5R deficiency leads to increased AT1R expression, sodium sensitivity, and hypertension.
Specific aim 1 will test the hypothesis that hypertension in D5-/- mice is, in part, caused by increased renal AT1R expression.
Specific aim 2 will test the hypothesis that the counter regulation of D1-like and AT1Rs are caused by several mechanisms including protein/protein interaction and proteasomal degradation. Knowledge of the mechanisms bywhich hypertension develops when D5R function is impaired may lead to the development of targeted therapeutics.
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