title: Deficient degradation of homotrimeric type I collagen, α1(I)3 glomerulopathy in oim mice.
abstract: Col1a2-deficient (oim) mice synthesize homotrimeric type I collagen due to nonfunctional proα2(I) collagen chains. Our previous studies revealed a postnatal, progressive type I collagen glomerulopathy in this mouse model, but the mechanism of the sclerotic collagen accumulation within the renal mesangium remains unclear. The recent demonstration of the resistance of homotrimeric type I collagen to cleavage by matrix metalloproteinases (MMPs), led us to investigate the role of MMP-resistance in the glomerulosclerosis of Col1a2-deficient mice. We measured the pre- and post-translational expression of type I collagen and MMPs in glomeruli from heterozygous and homozygous animals. Both the heterotrimeric and homotrimeric isotypes of type I collagen were equally present in whole kidneys of heterozygous mice by immunohistochemistry and biochemical analysis, but the sclerotic glomerular collagen was at least 95-98% homotrimeric, suggesting homotrimeric type I collagen is the pathogenic isotype of type I collagen in glomerular disease. Although steady-state MMP and Col1a1 mRNA levels increased with the disease progression, we found these changes to be a secondary response to the deficient clearance of MMP-resistant homotrimers. Increased renal MMP expression was not sufficient to prevent homotrimeric type I collagen accumulation.
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA. arpilgrim@path.wustl.edu
authors.forename: Anna M
authors.initials: AM
authors.lastname: Roberts-Pilgrim
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Myles
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Besch-Williford
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Brodeur
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Walker
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.forename: Craig L
authors.initials: CL
authors.lastname: Franklin
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001391:Azo Compounds; D024042:Collagen Type I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D006652:Histological Techniques; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D045726:Metalloproteases / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001391:Azo Compounds; D024042:Collagen Type I; D017931:DNA Primers; C009798:C.I. direct red 80; D045726:Metalloproteases