title: Early-onset diabetic E1-DN mice develop albuminuria and glomerular injury typical of diabetic nephropathy.
abstract: The transgenic E1-DN mice express a kinase-negative epidermal growth factor receptor in their pancreatic islets and are diabetic from two weeks of age due to impaired postnatal growth of β-cell mass. Here, we characterize the development of hyperglycaemia-induced renal injury in the E1-DN mice. Homozygous mice showed increased albumin excretion rate (AER) at the age of 10 weeks; the albuminuria increased over time and correlated with blood glucose. Morphometric analysis of PAS-stained histological sections and electron microscopy images revealed mesangial expansion in homozygous E1-DN mice, and glomerular sclerosis was observed in the most hyperglycaemic mice. The albuminuric homozygous mice developed also other structural changes in the glomeruli, including thickening of the glomerular basement membrane and widening of podocyte foot processes that are typical for diabetic nephropathy. Increased apoptosis of podocytes was identified as one mechanism contributing to glomerular injury. In addition, nephrin expression was reduced in the podocytes of albuminuric homozygous E1-DN mice. Tubular changes included altered epithelial cell morphology and increased proliferation. In conclusion, hyperglycaemic E1-DN mice develop albuminuria and glomerular and tubular injury typical of human diabetic nephropathy and can serve as a new model to study the mechanisms leading to the development of diabetic nephropathy.
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland ; Children's Hospital, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Mervi E
authors.initials: ME
authors.lastname: Hyvönen
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.
authors.forename: Vincent
authors.identifier: 0000-0002-2893-5479
authors.initials: V
authors.lastname: Dumont
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland ; Department of Pathology, HUSLAB, Helsinki University Central Hospital, 05850 Hyvinkää, Finland ; Department of Pathology, HUSLAB, Helsinki University Central Hospital, 00290 Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Tienari
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland ; Laboratory Animal Centre, University of Helsinki, 00790 Helsinki, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Lehtonen
authors.affiliation: Biomedicum Stem Cell Center, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Ustinov
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.
authors.forename: Marika
authors.identifier: 0000-0002-9226-2635
authors.initials: M
authors.lastname: Havana
authors.affiliation: Children's Hospital, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Jalanko
authors.affiliation: Children's Hospital, University of Helsinki, 00290 Helsinki, Finland ; Biomedicum Stem Cell Center, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Otonkoski
authors.affiliation: Children's Hospital, University of Helsinki, 00290 Helsinki, Finland ; Biomedicum Stem Cell Center, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Miettinen
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.
authors.forename: Sanna
authors.identifier: 0000-0003-4189-2415
authors.initials: S
authors.lastname: Lehtonen
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D036022:Capsid Proteins; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000473:pathology
chemical_list: D036022:Capsid Proteins; D008565:Membrane Proteins; C091717:VP3 protein, Chicken anemia virus; C113267:nephrin; D066246:ErbB Receptors