Animal Models for Studying the Genetics of Hypertension

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DESCRIPTION (provided by applicant): Our long-term objective remains to unravel the genetic complexities of essential hypertension and its complications. Specific aim (i) will test the hypothesis that blood pressure is controlled by many genetic and environmental factors that individually have only small effects but which in some combinations are detrimental and in others beneficial. Mice having pair-wise combinations of high and low expressing variants at genetic loci (Agtr1a, Npr1, and Pparg) in three different physiological systems will be generated. Telemetric blood pressure monitoring and quantitative RT-PCR will determine the effects on these mice of dietary salt and fat, and of relevant drug treatments, and how homeostatic compensations in their heart, kidneys, adrenals, liver and adipose tissues are affected. Specific aim (ii) will test the hypothesis that the renin gene outside the kidney is important in blood pressure maintenance. Ren1c-/- mice (which cannot produce renin anywhere), and mice with renin transgenes, RenTgs (which produce renin at different constant levels only in the liver) will be mated, and their Ren1c-/-RenTg progeny will be used to determine whether extra-renal renin can regulate blood pressure. We will transplant non-renin-producing kidneys from Ren1c-/-RenTg mice into wildtype mice to determine whether the Ren1c gene in extra-renal tissues, but not in the kidney, can control blood pressure. Specific aim (iii) will test the hypothesis that, during hypertensive cardiac hypertrophy, myocytes assume one of two states: hypertrophic but not expressing fetal genes, or hypertrophic and expressing fetal genes. We will induce and reverse hypertension in mice expressing fluorescent indicators of hypertrophy-responsive genes, and assess expression of the indicator and other genes in individual cells to determine whether genes switch concordantly or randomly in individual cells, and whether switched cells can resume their former state. Together these several studies should contribute to a better understanding of how genetic factors affect blood pressure, its homeostasis, and the complications of hypertension.