title: Characterization of the intrarenal renin-angiotensin system in experimental alport syndrome.
abstract: Blockade of the renin-angiotensin system attenuates the progression of experimental and clinical Alport syndrome (AS); however, the underlying mechanism(s) remains largely unknown. We evaluated the renin-angiotensin system in 4- and 7-week-old homozygous for collagen, type IV, α3 gene (Col4A3(-/-)) and wild-type mice, a model of AS characterized by proteinuria and progressive renal injury. Renal angiotensin (Ang) II levels increased, whereas renal Ang-(1-7) levels decreased in 7-week-old Col4a3(-/-) mice compared with age-matched controls; these changes were partially reversed by recombinant angiotensin-converting enzyme 2 (ACE2) treatment. The expression of both the angiotensinogen and renin protein increased in Col4a3(-/-) compared with wild-type mice. Consistent with the Ang-(1-7) levels, the expression and activity of kidney ACE2 decreased in 7-week-old Col4a3(-/-) mice. The urinary excretion rate of ACE2 paralleled the decline in tissue expression. Expression of an Ang II-induced gene, heme oxygenase-1, was up-regulated in the kidneys of 7-week-old Col4a3(-/-) mice compared with wild-type mice by microarray analysis. Heme oxygenase-1 (HO-1) protein expression was increased in kidneys of Col4a3(-/-) mice and normalized by treatment with ACE inhibitor. Urinary HO-1 excretion paralleled renal HO-1 expression. In conclusion, progressive kidney injury in AS is associated with changes in expression of intrarenal renin Ang system components and Ang peptides. HO-1 and ACE2 may represent novel markers of AS-associated kidney injury, whereas administration of recombinant ACE2 and/or Ang-(1-7) may represent novel therapeutic approaches in AS.
authors.affiliation: Department of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea. Electronic address: baedak@jnu.ac.kr.
authors.forename: Eun Hui
authors.initials: EH
authors.lastname: Bae
authors.affiliation: Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Konvalinka
authors.affiliation: Department of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Williams
authors.affiliation: Department of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Maksimowski
authors.affiliation: Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Genomic Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Song
authors.affiliation: Faculty of Medicine, Hộtel-DieuHộpital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rohan
authors.initials: R
authors.lastname: John
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Genomic Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: York
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012084:Renin-Angiotensin System / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2