title: The absence of intrarenal ACE protects against hypertension.
abstract: Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension.
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. romer.gonzalez@csmc.edu
authors.forename: Romer A
authors.initials: RA
authors.lastname: Gonzalez-Villalobos
authors.forename: Tea
authors.initials: T
authors.lastname: Janjoulia
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Fletcher
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Giani
authors.forename: Mien T X
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Anne D
authors.initials: AD
authors.lastname: Riquier-Brison
authors.forename: Dale M
authors.initials: DM
authors.lastname: Seth
authors.forename: Sebastien
authors.initials: S
authors.lastname: Fuchs
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.forename: Janos
authors.initials: J
authors.lastname: Peti-Peterdi
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McDonough
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D006973:Hypertension / Q000378:metabolism*; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008138:Loop of Henle / Q000378:metabolism; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D012084:Renin-Angiotensin System; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000378:metabolism; D014867:Water / Q000378:metabolism
chemical_list: D011955:Receptors, Drug; C578715:Slc12a1 protein, mouse; C578875:Slc12a3 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D014867:Water; D000804:Angiotensin II; D012964:Sodium; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester