Abstract
A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and can be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, which is indicative of differential susceptibility of organs to a hypertensive stimulus. The mesentery and heart exhibited the greatest sensitivity to damage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological changes induced in mesenteric resistance arteries suggest eutrophic remodeling of the vessels. Kinetic evidence suggests that locally activated plasma prorenin may play a critical role in mediating vascular injury. This model will facilitate studies of the cellular and genetic mechanisms underlying vascular injury and repair and provide a basis for the identification of novel therapeutic targets for vascular disease.
Highlights
Essential hypertension has a complex multifactorial phenotype
We have identified candidate loci in rats that may contribute to target organ damage and mortality in malignant hypertension (MH),1 a condition characterized by an accelerated rise in
Because the transgene was integrated on the Y chromosome in line TGR(Cyp1a1Ren2), it precludes the study of hypertension in females, but the model has wide applicability
Summary
The rat Cyp1a1 promoter was isolated by NotI-SalI double digestion of pAhIR1-LacZ Inducible Hypertension and Differential Vascular Sensitivity to yield an 11.5-kilobase fragment containing 5Ј-flanking regions exon 1 and part of exon 2. This was placed upstream of Ren-2 cDNA and an SV40 poly(A) signal in pBluescript SK2(ϩ) (see Fig. 1a) [10]. The injection fragment was excised by NotI-BssHII digestion and was introduced into Fischer F344 single-cell embryos by microinjection as described [11, 12]. The remaining lines, which exhibited varying degrees of hypertension in the absence of inducer, were not studied further
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