title: Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome.
abstract: Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase in the renin-angiotensin system that catalyzes the breakdown of angiotensin II to angiotensin 1-7. We have reported that ACE2 expression in the kidney is reduced in experimental Alport syndrome but the impact of this finding on disease progression has not been studied. Accordingly, we evaluated effects of murine recombinant ACE2 treatment in Col4a3 knockout mice, a model of Alport syndrome characterized by proteinuria and progressive renal injury. Murine recombinant ACE2 (0.5 mg/kg/day) was administered from four to seven weeks of age via osmotic mini-pump. Pathological changes were attenuated by murine recombinant ACE2 treatment which ameliorated kidney fibrosis as shown by decreased expression of COL1α1 mRNA, less accumulation of extracellular matrix proteins, and inhibition of transforming growth factor-β signaling. Further, increases in proinflammatory cytokine expression, macrophage infiltration, inflammatory signaling pathway activation, and heme oxygenase-1 levels in Col4a3 knockout mice were also reduced by murine recombinant ACE2 treatment. Lastly, murine recombinant ACE2 influenced the turnover of renal ACE2, as it suppressed the expression of tumor necrosis factor-α converting enzyme, a negative regulator of ACE2. Thus, treatment with exogenous ACE2 alters angiotensin peptide metabolism in the kidneys of Col4a3 knockout mice and attenuates the progression of Alport syndrome nephropathy.
authors.affiliation: Department of Medicine and Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Eun Hui
authors.initials: EH
authors.lastname: Bae
authors.affiliation: Department of Medicine and Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Medicine and Institute of Medical Science, University of Toronto, Toronto, Canada. Electronic address: vanessa.williams@mail.utoronto.ca.
authors.forename: Vanessa R
authors.initials: VR
authors.lastname: Williams
authors.affiliation: Department of Medicine and Institute of Medical Science, University of Toronto, Toronto, Canada; Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Konvalinka
authors.affiliation: Department of Medicine and Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: Divisions of Nephrology and Genomic Medicine, University Health Network and University of Toronto, Toronto, Canada.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Pathology, University Health Network and University of Toronto, Toronto, Canada.
authors.forename: Rohan
authors.initials: R
authors.lastname: John
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: Divisions of Nephrology and Genomic Medicine, University Health Network and University of Toronto, Toronto, Canada.
authors.forename: York
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Medicine and Institute of Medical Science, University of Toronto, Toronto, Canada; Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, Canada.
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024141:Collagen Type IV / Q000172:deficiency / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000008:administration & dosage*; D010641:Phenotype; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000809:Angiotensins; D001324:Autoantigens; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024141:Collagen Type IV; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D011994:Recombinant Proteins; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C057112:type IV collagen alpha3 chain; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: Alport syndrome; TNFα-converting enzyme; angiotensin-converting enzyme 2; renal fibrosis; renin-angiotensin system