Transgenes, hypotheses, and hypertension.

In complex systems such as blood pressure homeostasis, physiological compensatory mechanisms effectively mask any perturbations to the status quo. When these mechanisms fail to restore homeostasis, the presenting phenotype may be far removed from the initial perturbation, making it difficult or even impossible to unravel the underlying etiology. This is the case with hypertensive rat models such as the spontaneously hypertensive rat (SHR), where a vast body of knowledge has been accumulated, but progress has been slow in identifying the true underlying cause or causes of hypertension. Instead of establishing genetic models by phenotypic selection, it is possible via transgenesis to make phenotypic models through the use of selected genes or alleles. However, in all but the very simplest transgenic manipulations, it still may be difficult to distinguish "cause" from "effect." When single genetic alterations are introduced into the germline, the researcher at least has a clear starting point from which to unravel the phenotypic response. Such is the case with the TGR (mRen-2)27 transgenic rat, which was generated by the stable introduction of the mouse Ren-2 renin gene into the rat germline, with the resulting phenotype of elevated blood pressure. This transgenic strain was constructed with three specific aims in mind, namely, (1) to establish transgenic technology in this species, giving greater flexibility for genetic experimentation in areas such as cardiovascular research, neurobiology, and physiology; (2) to directly test the ability of the granular convoluted tubule cells of the rat submandibular gland (which do not express endogenous rat renin) to express the mouse Ren-2 gene, a gene expressed at high levels in mouse granular convoluted tubule cells; and (3) to examine whether the Ren-2 enzyme has activity in vivo and could affect blood pressure per se. Although it was not specifically designed to model essential or any other form of human hypertension, this rat strain has the potential to yield insight into the mechanisms whereby apparent low plasma renin levels can be associated with hypertension. The initial findings that plasma and kidney renin levels were normal to low suggested negative feedback on the endocrine renin-angiotensin system (RAS), and in situ hybridization of transgenic kidneys, together with immunohistochemical analysis, indicated that renal renin expression was strongly suppressed. Paradoxically, plasma prorenin levels were extremely elevated. Blood