title: IGF-1 decreases collagen degradation in diabetic NOD mesangial cells: implications for diabetic nephropathy.
abstract: Nonobese diabetic (NOD) mice develop glomerulosclerosis shortly after the onset of diabetes. We showed that mesangial cells (MCs) from diabetic mice exhibited a stable phenotypic switch, consisting of both increased IGF-1 synthesis and proliferation (Elliot SJ, Striker LJ, Hattori M, Yang CW, He CJ, Peten EP, Striker GE: Mesangial cells from diabetic NOD mice constitutively secrete increased amounts of insulin-like growth factor-I. Endocrinology 133:1783-1788, 1993). Because the extracellular matrix (ECM) accumulation in diabetic glomerulosclerosis may be partly due to decreased degradation, we examined the effect of excess IGF-1 on collagen turnover and the activity of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) in diabetic and nondiabetic NOD-MC. Total collagen degradation was reduced by 58 +/- 18% in diabetic NOD-MCs, which correlated with a constitutive decrease in MMP-2 activity and mRNA levels, and nearly undetectable MMP-9 activity and mRNA. TIMP levels were slightly decreased in diabetic NOD-MC. The addition of recombinant IGF-1 to nondiabetic NOD-MC resulted in a decrease in MMP-2 and TIMP activity. Furthermore, treatment of diabetic NOD-MC with a neutralizing antibody against IGF-1 increased the latent form, and restored the active form, of MMP-2. In conclusion, the excessive production of IGF-1 contributes to the altered ECM turnover in diabetic NOD-MC, largely through a reduction of MMP-2 activity. These data suggest that IGF-1 could be a major contributor to the development of diabetic glomerulosclerosis.
authors.affiliation: Department of Medicine, University of Miami School of Medicine, Florida 33101, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lupia
authors.forename: S J
authors.initials: SJ
authors.lastname: Elliot
authors.forename: O
authors.initials: O
authors.lastname: Lenz
authors.forename: F
authors.initials: F
authors.lastname: Zheng
authors.forename: M
authors.initials: M
authors.lastname: Hattori
authors.forename: G E
authors.initials: GE
authors.lastname: Striker
authors.forename: L J
authors.initials: LJ
authors.lastname: Striker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology; D005260:Female; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D007797:Laminin / Q000235:genetics; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D007797:Laminin; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9