Paradoxical regulation of short promoter human renin transgene by angiotensin ii.
We previously reported the generation of transgenic mice containing the entire human renin gene with a 900-bp promoter. To determine whether all the required elements for angiotensin II-mediated suppression of human renin are present in these mice, angiotensin II was chronically infused by means of osmotic minipump at both low and high doses, 200 and 1000 ng/kg per minute, respectively. Blood pressure was measured by tail-cuff, and kidney renin mRNA levels were quantitated using ribonuclease protection assays. Blood pressure was unchanged in mice receiving either vehicle or low-dose angiotensin II infusion but was increased by approximately 40 mm Hg with the higher dose of angiotensin II. Mouse renin mRNA decreased by >60% during both pressor and nonpressor angiotensin II infusion. Human renin mRNA was not suppressed by nonpressor angiotensin II and was paradoxically increased 1.9-fold by pressor angiotensin II. The lack of upregulation during nonpressor angiotensin II suggested that the increase might be pressure-mediated. To test this, the angiotensin II-induced increase in blood pressure was prevented by coadministration of the vasodilator, hydralazine (15 mg/kg per day). Hydralazine alone decreased blood pressure (-27+/-3 mm Hg) and increased mouse renin mRNA 2.4-fold. Human renin mRNA was unresponsive to this vasodilator-induced fall in pressure and despite the normalization of blood pressure by hydralazine, high-dose angiotensin II still caused a 2.1-fold increase in human renin mRNA. Thus, the first 900 bp of the human renin promoter does not contain all the elements required for appropriate angiotensin II-mediated suppression of human renin mRNA.
Departments of Internal Medicine and Physiology & Biophysics, University of Iowa College of Medicine, Iowa City, Iowa, USA.
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D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D015918:Infusion Pumps, Implantable; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D014665:Vasodilator Agents / Q000494:pharmacology
D012333:RNA, Messenger; D014665:Vasodilator Agents; D000808:Angiotensinogen; D000804:Angiotensin II; D006830:Hydralazine; D012083:Renin