Novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice

We tested the hypothesis that the tissue-specific intrarenal renin-angioten sin system (RAS) can participate in the regulation of blood pressure indepe ndently of its endocrine counterpart, by generating two transgenic models t hat differ in their tissue-specific expression of human angiotensinogen (AG T). Human AGT expression was driven by its endogenous promoter in the syste mic model and by the kidney androgen-regulated protein promoter in the kidn ey-specific model. Using molecular, biochemical, and physiological measurem ents, we demonstrate that human AGT mRNA and protein are restricted to the kidney in the kidney-specific model. Plasma ANG II was elevated in the syst emic model but not in the kidney-specific model. Nevertheless, blood pressu re was markedly elevated in both the systemic and kidney-specific transgeni c mice. Acute administration of the selective ANG II AT-1 receptor antagoni st losartan lowered blood pressure in the systemic model but not in the kid ney-specific model. These results provide evidence for the potential import ance of the intrarenal RAS in blood pressure regulation by showing that exp ression of AGT specifically in the kidney leads to chronic hypertension ind ependently of the endocrine RAS.