title: Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice.
abstract: Angiotensin-converting enzyme 2 (ACE2) degrades angiotensin II to angiotensin-(1-7) and is expressed in podocytes. Here we overexpressed ACE2 in podocytes in experimental diabetic nephropathy using transgenic methods where a nephrin promoter drove the expression of human ACE2. Glomeruli from these mice had significantly increased mRNA, protein, and activity of ACE2 compared to wild-type mice. Male mice were treated with streptozotocin to induce diabetes. After 16 weeks, there was no significant difference in plasma glucose levels between wild-type and transgenic diabetic mice. Urinary albumin was significantly increased in wild-type diabetic mice at 4 weeks, whereas albuminuria in transgenic diabetic mice did not differ from wild-type nondiabetic mice. However, this effect was transient and by 16 weeks both transgenic and nontransgenic diabetic mice had similar rates of proteinuria. Compared to wild-type diabetic mice, transgenic diabetic mice had an attenuated increase in mesangial area, decreased glomerular area, and a blunted decrease in nephrin expression. Podocyte numbers decreased in wild-type diabetic mice at 16 weeks, but were unaffected in transgenic diabetic mice. At 8 weeks, kidney cortical expression of transforming growth factor-β1 was significantly inhibited in transgenic diabetic mice as compared to wild-type diabetic mice. Thus, the podocyte-specific overexpression of human ACE2 transiently attenuates the development of diabetic nephropathy.
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Renisha
authors.initials: R
authors.lastname: Nadarajah
authors.forename: Rosangela
authors.initials: R
authors.lastname: Milagres
authors.forename: Marc
authors.initials: M
authors.lastname: Dilauro
authors.forename: Alex
authors.initials: A
authors.lastname: Gutsol
authors.forename: Fengxia
authors.initials: F
authors.lastname: Xiao
authors.forename: Joseph
authors.initials: J
authors.lastname: Zimpelmann
authors.forename: Chris
authors.initials: C
authors.lastname: Kennedy
authors.forename: Jan
authors.initials: J
authors.lastname: Wysocki
authors.forename: Daniel
authors.initials: D
authors.lastname: Batlle
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burns
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005919:Glomerular Filtration Rate; D005920:Glomerular Mesangium / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism*; D050199:Podocytes / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2