Abstract
A novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice
Davisson,Robin L.; Ding,Yueming; Stec,David E.; Catterall,James F.; Sigmund,Curt D.
Physiological Genomics 1(1): 3-9
Publication date: 1999
We testedthe hypothesis that the tissue-specific intrarenal renin-angiotensinsystem (RAS) can participate in the regulation of blood pressureindependently of its endocrine counterpart, by generating twotransgenic models that differ in their tissue-specific expressionof human angiotensinogen (AGT). Human AGT expression was drivenby its endogenous promoter in the systemic model and by thekidney androgen-regulated protein promoter in the kidney-specificmodel. Using molecular, biochemical, and physiological measurements,we demonstrate that human AGT mRNA and protein are restrictedto the kidney in the kidney-specific model. Plasma ANG II waselevated in the systemic model but not in the kidney-specificmodel. Nevertheless, blood pressure was markedly elevated inboth the systemic and kidney-specific transgenic mice. Acuteadministration of the selective ANG II AT-1 receptor antagonistlosartan lowered blood pressure in the systemic model but notin the kidney-specific model. These results provide evidencefor the potential importance of the intrarenal RAS in bloodpressure regulation by showing that expression of AGT specificallyin the kidney leads to chronic hypertension independently ofthe endocrine RAS.
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