Hypertension affects approximately 25% of the adult population in the United States and is an important risk factor for death from stroke, myocardial infarction, congestive heart failure, and chronic kidney disease. The distal convoluted tubule (DCT) of the kidney plays a critical role in the reabsorption of sodium (primarily via the sodium chloride cotransporter, NCC) and hence in regulation of blood pressure. This is best illustrated by the disease Pseudohypoaldosteronism type II (PHAII), characterized by hyperkalemic hypertension, caused by gene defects in regulators of NCC that enhance its activity. PHAII is remediable by treatment with thiazide diuretics, which specifically inhibit NCC. Importantly, thiazide diuretics are the first therapuetic choice in the majority of hypertensive patients, not just those with PHAII. There is controversy as to whether PHAII is caused solely by altered NCC activity, or whether dysregulation of other ion channels and transporters is involved. There is also evidence that NCC activity is regulated by the mineralocorticoid hormone aldosterone. Since levels of the mineralocorticoid receptor are low in the DCT, the physiological effects of aldosterone on this kidney segment are unclear. This proposal aims to characterize two mouse models to give better insight into PHAII and DCT function. (1) Generation and analysis of mice over-expressing NCC in the DCT, as a possible model of PHAII. Blood pressure measurements, and analysis of urinary and plasma electrolytes will be performed in conjunction with proteomic analysis. These parameters will be studied on a normal diet, and on diets in which sodium and potassium levels have been modified. The ability of thiazides to normalize any defects will be assessed. (2) Inducible, DCT-specific disruption of the mineralocorticoid receptor, to gain insight into the role of aldosterone in DCT function. These mice will be generated, and similarly to aim (1), blood pressure and electrolyte measurements will be performed under various dietary conditions. A didactic program in nephrology and in the responsible conduct of research will complement the research program to assist the candidate in achieving his long term career goal of performing independent basic nephrology research in an academic setting. Dr. David Ellison, a leader in DCT physiology will mentor the candidate's scientific development, as will input from Dr. Donald Kohan, a leader in mouse models of hypertension.
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