Appropriate regulation of renin and blood pressure in 45-kb human renin/human angiotensinogen transgenic mice

Abstract

The renin-angiotensin system is normally subject to servo control mechanisms that suppress plasma renin levels in response to increased blood pressure and increase plasma renin levels when blood pressure falls. In most species, renin is rate limiting, and angiotensinogen circulates at a concentration close to the K(m), so varying the concentration of either can affect the rate of angiotensin formation. However, only the plasma renin level responds to changes in blood pressure and sodium balance to maintain blood pressure homeostasis. Therefore, the high plasma human renin levels and the hypertension of mice and rats containing both human renin and angiotensinogen transgenes indicate inappropriate regulation of renin and blood pressure. These anomalies led us to develop new lines of transgenic mice with a longer human renin gene fragment (45 kb) than earlier lines (13 to 15 kb). Unlike their predecessors, the 45-kb hREN mice secrete human renin only from the kidneys, and both the human and mouse renins respond appropriately to physiological stimuli. To determine whether blood pressure is also regulated appropriately, we crossed these new 45-kb hREN mice with mice containing the human angiotensinogen gene. All doubly transgenic mice were normotensive like their singly transgenic and nontransgenic littermates. Moreover, among doubly transgenic mice, both human and mouse plasma renin concentrations were suppressed relative to the singly transgenic 45-kb hREN mice. These findings demonstrate the importance of appropriate cell and tissue specificity of gene expression in constructing transgenic models and affirm the pivotal role played by renal renin secretion in blood pressure control.