It is widely recognized that an elevated systemic blood pressure is associated with increased mortality and morbidity. This morbidity and the high incidence of hypertension within the US population combine to make hypertension the major indication for the use of prescription drugs and visits to physician's offices. Our work has focused on the renin- angiotensin system (RAS), one of the central physiological mechanisms that maintains pressure and volume homeostasis. The RAS relies on the sequential action of two enzymes, renin and angiotensin-converting enzyme (ACE) to produce the potent octapeptide, angiotensin II (AII). At present the blockade of AII formation is only possible using an ACE inhibitor. ACE is a cell membrane peptidase that influences blood pressure through at least two mechanisms, the conversion of angiotensin I to angiotensin II and the inactivation of the vasodilator, bradykinin. ACE inhibitors not only lower the blood pressure of hypertensives with high renin levels, but also the 85% of essential hypertensives with normal or low renin levels. Converting enzyme inhibitors, used in experimental models of diabetes to control glomerular capillary hypertension, markedly reduce progressive renal disease. Thus ACE is a central enzyme in the biology of blood pressure control. ACE has been studied for many years and there is now overwhelming evidence that the ACE protein produced by endothelium, renal tubular epithelium and other relevant somatic tissues is a single protein chain, the product of a single gene within the mouse or human genomes. This isozyme is referred to as somatic ACE. A second, smaller isozyme of ACE has been identified within germ cells of the testis and is referred to as testis ACE. These two isozymes result from two distinct promoter regions within the ACE gene and thus are the result of tissue specific regulation of RNA transcription. This grant proposes to analyze the transcription of the ACE gene, to focus on the biochemistry and molecular biology of why the kidney and other somatic tissues make a different isozyme of ACE than that produced by developing germ cells. An analysis of the control of ACE transcription will add to the understanding of tissue specific gene expression and the mechanisms of homeostatic control of systemic blood pressure.
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