Transgenic models of hypertension: useful tools or unusual toys?

Editorial Recent linkage studies in humans with essential hypertension and in animal models of spontaneous hypertension have suggested that genetically determined variation in the activity of the renin-angiotensin system may contribute to inherited variations in blood pressure (1, 2). While it is remarkable that most of the positive linkage studies of hypertension to date have implicated chromosome regions that contain genes of the renin-angiotensin system, such studies cannot prove that genetically determined alterations in the renin-angiotensin system contribute to the pathogenesis of spontaneous forms of hyper-tension. However, selective breeding experiments and gene transfer techniques may be used to investigate directly whether variation in specific DNA sequences can affect blood pressure. In the current issue of The Journal ofClinical Investigation Peters et al. report studies in the transgenic hypertensive rat TGR(mREN2)27, a novel experimental model of hyperten-sion that was derived by the transgenic expression of a mouse renin gene (Ren-2 d) on the genetic background of noninbred Sprague-Dawley rats (3, 4). The creation of this transgenic hypertensive rat was an impressive accomplishment and it is likely that the model will be useful for a variety of purposes, including pharmacologic studies, drug testing, and the investigation of blood pressure control mechanisms. But can these kinds of transgenic models provide any insight into the patho-genesis of spontaneous forms of hypertension? Although the transgenic hypertensive rat clearly demonstrates that overexpression of the mouse renin gene in a Sprague-Dawley rat can give rise to increased blood pressure, the relevance of this model to natural forms of spontaneous hypertension remains uncertain. At first glance, it might seem predictable that overexpression of the renin gene would cause increased blood pressure and that the model would provide no more insight into the pathogenesis of spontaneous forms of hypertension than would hypertensive models produced by renal artery clipping or by continuous infusions ofangiotensin II. In the transgenic hypertensive rat, however, the mechanism of increased blood pressure has not proven to be immediately obvious. This model is characterized by low levels of plasma renin activity and decreased renin gene expression in the kidneys. Thus, the hypertension does not appear to be simply caused by increased activity of the circulating or renal renin-angiotensin systems. A striking feature of the transgenic hypertensive rat is the markedly increased expression of the mouse renin gene in the adrenals. Peters and colleagues have shown that adrenal expression ofthe mouse renin transgene gives rise to considerable …