Research Project
Grant-in-Aid for Scientific Research (C)
Chronic elevations of circulating angiotensin II (Ang II) cause sustained hypertension and enhanced accumulation of intrarenal Ang II by an Ang II type 1 receptor (AT1 receptor) -dependent process. Previous studies showed that the C-terminal cytoplasmic domain of AT1 receptor is involved in the control of receptor internalization and in linking receptor-mediated signal transduction to the specific biological response. We previously cloned a novel molecule ATRAP (AT1 receptor-associated protein) that specifically interacts with C-terminal of AT1 receptor. The results of previous in vitro studies showed that ATRAP specifically inhibits AT1 receptor signaling by constitutive activation of AT1 receptor internalization to decrease cell surface AT1 receptor number. The present study tested the hypothesis that chronic elevations in circulating Ang II regulate ATRAP protein expression in a tissue-specific manner. C57BL6 mice were infused with Ang II (1,000 ng/kg/min)or vehicle subcutaneously f … More or 14 days via osmotic minipump. On day 12, systolic blood pressure averaged 176+/-1.0 mm Hg in Ang II-infused mice compared with mice given vehicle (122+/-4 mm Hg) .Western blot analysis using the anti-AT1 receptor and anti-ATRAP antibodies was performed. The results showed that AT1 receptor protein levels in the kidney and liver were comparable in Ang II- and vehicle-infused mice. In contrast, ATRAP protein levels were significantly decreased in the kidney of Ang II-infused mice (51% decrease; P<0.05). ATRAP protein levels in the liver were also similar in the two groups. Therefore, these "results indicate that renal and liver AT1 receptor gene expression is maintained but renal ATRAP gene expression is specifically suppressed in Ang II-induced hypertension. The renal-specific down-regulation of the ratios of ATRAP/AT1 receptor expression by Ang II infusion causes the relative predominance of AT1 receptor signaling over inhibition by ATRAP in the kidney and thus allows the sustained effects of chronic elevations in Ang II to elicit progressive increases in blood pressure. Less
All 2008 2007 2006 2005
All Journal Article (15 results) (of which Peer Reviewed: 6 results) Presentation (2 results) Book (3 results)
Hypertension 50
Pages: 926-932
Am J Physiol Renal Physiol 292
Curr Hypertens Rep 9
Pages: 121-127
Am J Physiol Renal Physiol. 292
Kidney International 69
Pages: 488-494
Biochem Biophys Res Commun 339
Pages: 1129-1137
J Clin Invest. 116
Pages: 3026-3034
Int J Neuropsychopharmacol. 9
Pages: 635-636
Clinical and Experimental Hypertension 27
Pages: 139-147
FEBS Letters 579
Pages: 1579-1586
