title: Renal proximal tubule angiotensin AT1A receptors regulate blood pressure.
abstract: All components of the renin angiotensin system necessary for ANG II generation and action have been reported to be present in renal proximal convoluted tubules. Given the close relationship between renal sodium handling and blood pressure regulation, we hypothesized that modulating the action of ANG II specifically in the renal proximal tubules would alter the chronic level of blood pressure. To test this, we used a proximal tubule-specific, androgen-dependent, promoter construct (KAP2) to generate mice with either overexpression of a constitutively active angiotensin type 1A receptor transgene or depletion of endogenous angiotensin type 1A receptors. Androgen administration to female transgenic mice caused a robust induction of the transgene in the kidney and increased baseline blood pressure. In the receptor-depleted mice, androgen administration to females resulted in a Cre recombinase-mediated deletion of angiotensin type 1A receptors in the proximal tubule and reduced blood pressure. In contrast to the changes observed at baseline, there was no difference in the blood pressure response to a pressor dose of ANG II in either experimental model. These data, from two separate mouse models, provide evidence that ANG II signaling via the type 1A receptor in the renal proximal tubule is a regulator of systemic blood pressure under baseline conditions.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Li
authors.forename: Eric T
authors.initials: ET
authors.lastname: Weatherford
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Davis
authors.forename: Henry L
authors.initials: HL
authors.lastname: Keen
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Allen
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D005260:Female; D019426:Integrases / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000728:Androgens; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C045073:Cre recombinase; D019426:Integrases