title: Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress.
abstract: Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence and Neurosciences Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana hxia1@lsuhsc.edu.
authors.forename: Huijing
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence and Neurosciences Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Thyago Moreira
authors.initials: TM
authors.lastname: de Queiroz
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence and Neurosciences Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Sriramula
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence and Neurosciences Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence and Neurosciences Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Tanya
authors.initials: T
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence and Neurosciences Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Imran N
authors.initials: IN
authors.lastname: Mungrue
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence and Neurosciences Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D064791:Desoxycorticosterone Acetate; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D057967:Infusions, Intraventricular; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010286:Paraventricular Hypothalamic Nucleus / Q000201:enzymology / Q000503:physiopathology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D017673:Sodium Chloride, Dietary; D013356:Subfornical Organ / Q000201:enzymology / Q000503:physiopathology; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D017673:Sodium Chloride, Dietary; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D064791:Desoxycorticosterone Acetate; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: angiotensin-converting enzyme type 2; blood pressure; central nervous system; deoxycorticosterone acetate; neurogenic hypertension