title: Diabetes-induced alterations in tissue collagen and carboxymethyllysine in rat kidneys: Association with increased collagen-degrading proteinases and amelioration by Cu(II)-selective chelation.
abstract: Advanced glycation end-products (AGEs) comprise a group of non-enzymatic post-translational modifications of proteins and are elevated in diabetic tissues. AGE-modification impairs the digestibility of collagen in vitro but little is known about its relation to collagen-degrading proteinases in vivo. N(ε)-carboxymethyllysine (CML) is a stable AGE that forms on lysyl side-chains in the presence of glucose, probably via a transition metal-catalysed mechanism. Here, rats with streptozotocin-induced diabetes and non-diabetic controls were treated for 8weeks with placebo or the Cu(II)-selective chelator, triethylenetetramine (TETA), commencing 8weeks after disease induction. Actions of diabetes and drug treatment were measured on collagen and collagen-degrading proteinases in kidney tissue. The digestibility and CML content of collagen, and corresponding levels of mRNAs and collagen, were related to changes in collagen-degrading-proteinases. Collagen-degrading proteinases, cathepsin L (CTSL) and matrix metalloproteinase-2 (MMP-2) were increased in diabetic rats. CTSL-levels correlated strongly and positively with increased collagen-CML levels and inversely with decreased collagen digestibility in diabetes. The collagen-rich mesangium displayed a strong increase of CTSL in diabetes. TETA treatment normalised kidney collagen content and partially normalised levels of CML and CTSL. These data provide evidence for an adaptive proteinase response in diabetic kidneys, affected by excessive collagen-CML formation and decreased collagen digestibility. The normalisation of collagen and partial normalisation of CML- and CTSL-levels by TETA treatment supports the involvement of Cu(II) in CML formation and altered collagen metabolism in diabetic kidneys. Cu(II)-chelation by TETA may represent a treatment option to rectify collagen metabolism in diabetes independent of alterations in blood glucose levels.
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brings
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Yee S
authors.initials: YS
authors.lastname: Choong
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hogl
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Martin
authors.initials: M
authors.lastname: Middleditch
authors.affiliation: The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand; The School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Meder
authors.initials: M
authors.lastname: Kamalov
authors.affiliation: The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand; The School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Deming
authors.initials: D
authors.lastname: Gong
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand; Centre for Advanced Discovery and Experimental Therapeutics, NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, School of Biomedicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Department of Pharmacology, Division of Medical Sciences, University of Oxford, Oxford, UK. Electronic address: g.cooper@auckland.ac.nz.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000378:metabolism* / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D010447:Peptide Hydrolases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D014266:Trientine / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D013311:Streptozocin; C048496:N(6)-carboxymethyllysine; D003300:Copper; D003094:Collagen; D010447:Peptide Hydrolases; D008239:Lysine; D014266:Trientine
keywords: Advanced glycation end-product; Autoxidative glycation; Cathepsin L; Collagen; Matrix metalloproteinase-2; Triethylenetetramine