title: Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity.
abstract: Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, is central to the development of salt sensitivity in this setting. Two mouse models were used: it-ACE mice in which ACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L-NAME salt challenge. While both wild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, is essential for renal angiotensin II accumulation and salt-sensitive hypertension.
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Giani
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Eriguchi
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Bernstein
authors.affiliation: Cedars-Sinai Animal Models Core, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Katsumata
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Xiao Z
authors.initials: XZ
authors.lastname: Shen
authors.affiliation: Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McDonough
authors.affiliation: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, USA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA; CVMET Research Unit, Pfizer, Inc., Cambridge, Massachusetts, USA. Electronic address: romer.gonzalezvillalobos@pfizer.com.
authors.forename: Romer A
authors.initials: RA
authors.lastname: Gonzalez-Villalobos
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D062186:Arterial Pressure; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007684:Kidney Tubules / Q000201:enzymology* / Q000503:physiopathology; D008099:Liver / Q000201:enzymology; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester; D009318:Natriuresis; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D065667:Renal Elimination; D012084:Renin-Angiotensin System / Q000235:genetics; D017673:Sodium Chloride, Dietary; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064486:Solute Carrier Family 12, Member 3 / Q000378:metabolism; D013997:Time Factors
chemical_list: D053503:Epithelial Sodium Channels; C578875:Slc12a3 protein, mouse; D017673:Sodium Chloride, Dietary; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D000804:Angiotensin II; C522402:Ace3 protein, mouse; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester
keywords: angiotensin II; angiotensin-converting enzyme; hypertension; renal sodium transporters