title: Lack of collagen XVIII long isoforms affects kidney podocytes, whereas the short form is needed in the proximal tubular basement membrane.
abstract: Collagen XVIII is characterized by three variant N termini, an interrupted collagenous domain, and a C-terminal antiangiogenic domain known as endostatin. We studied here the roles of this collagen type and its variant isoforms in the mouse kidney. Collagen XVIII appeared to be in a polarized orientation in the tubular basement membranes (BMs), the endostatin domain embedded in the BM, and the N terminus residing at the BM-fibrillar matrix interface. In the case of the glomerular BM (GBM), collagen XVIII was expressed in different isoforms depending on the side of the GBM. The orientation appeared polarized here, too, both the endothelial promoter 1-derived short variant of collagen XVIII and the epithelial promoter 2-derived longer variants having their C-terminal endostatin domains embedded in the BM and the N termini at the respective BM-cell interfaces. In addition to loosening of the proximal tubular BM structure, the Col18a1(-/-) mice showed effacement of the glomerular podocyte foot processes, and microindentation studies showed changes in the mechanical properties of the glomeruli, the Col18a1(-/-) glomeruli being ∼30% softer than the wild-type. Analysis of promoter-specific knockouts (Col18a1(P1/P1) and Col18a1(P2/P2)) indicated that tubular BM loosening is due to a lack of the shortest isoform, whereas the glomerular podocyte effacement was due to a lack of the longer isoforms. We suggest that lack of collagen XVIII may also have disparate effects on kidney function in man, but considering the mild physiological findings in the mutant mice, such effects may manifest themselves only late in life or require other compounding molecular changes.
authors.affiliation: From the Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell Matrix Research and.
authors.forename: Aino I
authors.initials: AI
authors.lastname: Kinnunen
authors.affiliation: Department of Pathology, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: From the Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell Matrix Research and.
authors.forename: Harri
authors.initials: H
authors.lastname: Elamaa
authors.affiliation: From the Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell Matrix Research and.
authors.forename: Lotta
authors.initials: L
authors.lastname: Seppinen
authors.affiliation: the Departments of Medicine and Physiology, Louis Stokes Veterans Affairs Medical Center and Rammelkamp Center for Research and Education, Case Western Reserve University, Cleveland, 44106 Ohio.
authors.forename: R Tyler
authors.initials: RT
authors.lastname: Miller
authors.affiliation: the Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan, and.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Ninomiya
authors.affiliation: the Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, 19104 Pennsylvania.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Janmey
authors.affiliation: From the Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell Matrix Research and. Electronic address: taina.pihlajaniemi@oulu.fi.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
mesh_terms: D000818:Animals; D004548:Elasticity; D005260:Female; D024022:Fibrillar Collagens / Q000235:genetics / Q000378:metabolism*; D050533:Glomerular Basement Membrane / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D024022:Fibrillar Collagens; D020033:Protein Isoforms