title: Glibenclamide induces collagen IV catabolism in high glucose-stimulated mesangial cells.
abstract: We have shown the full prevention of mesangial expansion in insulin-deficient diabetic rats by treatment with clinically-relevant dosages of glibenclamide (Glib). Studies in mesangial cells (MCs) also demonstrated reduction in the high glucose (HG)-induced accumulation of collagens, proposing that this was due to increased catabolism. In the present study, we investigated the signaling pathways that may be implicated in Glib action. Rat primary MCs were exposed to HG for 8 weeks with or without Glib in therapeutic (0.01 μM) or supratherapeutic (1.0 μM) concentrations. We found that HG increased collagen IV protein accumulation and PAI-1 mRNA and protein expression, in association with decreased cAMP generating capacity and decreased PKA activity. Low Glib increased collagen IV mRNA but fully prevented collagen IV protein accumulation and PAI-1 overexpression while enhancing cAMP formation and PKA activity. MMP2 mRNA, protein expression and gelatinolytic activity were also enhanced. High Glib was, overall, ineffective. In conclusion, low dosage/concentration Glib prevents HG-induced collagen accumulation in MC by enhancing collagen catabolism in a cAMP-PKA-mediated PAI-1 inhibition.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Henry Ford Hospital, Detroit, MI 48202, USA. lzhu1@hfhs.org
authors.forename: Liping
authors.initials: L
authors.lastname: Zhu
authors.forename: Pedro
authors.initials: P
authors.lastname: Cortes
authors.forename: Clare
authors.initials: C
authors.lastname: Hassett
authors.forename: David W
authors.initials: DW
authors.lastname: Taube
authors.forename: Jerry
authors.initials: J
authors.lastname: Yee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology* / Q000627:therapeutic use; D006943:Hyperglycemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D024141:Collagen Type IV; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D005905:Glyburide