title: RAGE- and TGF-beta receptor-mediated signals converge on STAT5 and p21waf to control cell-cycle progression of mesangial cells: a possible role in the development and progression of diabetic nephropathy.
abstract: The molecular events associated with acute and chronic exposure of mesangial cells (MC) to hyperglycemia were evaluated. We found that, unlike high glucose (HG) and Amadori adducts, advanced glycation end products (AGE) and transforming growth factor-beta (TGF-beta) induced p21waf expression and accumulation of MC in G0/G1. TGF-beta1 blockade inhibited AGE-mediated collagen production but only partially affected AGE-induced p21waf expression and cell-cycle events, indicating that AGE by binding to AGE receptor (RAGE) per se could control MC growth. Moreover, AGE and TGF-beta treatment led to the activation of the signal transduction and activators of transcription (STAT)5 and the formation of a STAT5/p21SIE2 complex. The role of STAT5 in AGE- and TGF-beta-mediated p21waf expression and growth arrest, but not collagen production, was confirmed by the expression of the dominant negative STAT5 (DeltaSTAT5) or the constitutively activated STAT5 (1*6-STAT5) constructs. Finally, in p21waf-/- fibroblasts both AGE and TGF-beta failed to inhibit cell-cycle progression. A potential in vivo role of these mechanisms was sustained by the increasing immunoreactivity for the activated STAT5 and p21(waf) in kidney biopsies from early to advanced stage of diabetic nephropathy. Our data indicate that AGE- and TGF-beta-mediated signals, by converging on STAT5 activation and p21waf expression, may regulate MC growth.
authors.affiliation: Department of Internal Medicine, University of Torino, Corso Dogliotti 14, Torino, Italy. mariafelice.brizzi@unito.it
authors.forename: Maria Felice
authors.initials: MF
authors.lastname: Brizzi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dentelli
authors.forename: Arturo
authors.initials: A
authors.lastname: Rosso
authors.forename: Cristina
authors.initials: C
authors.lastname: Calvi
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambino
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cassader
authors.forename: Gennaro
authors.initials: G
authors.lastname: Salvidio
authors.forename: Giacomo
authors.initials: G
authors.lastname: Deferrari
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
authors.forename: Luigi
authors.initials: L
authors.lastname: Pegoraro
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pagano
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavallo-Perin
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D006984:Hypertrophy; D008894:Milk Proteins / Q000235:genetics; D009404:Nephrotic Syndrome / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D017127:Glycation End Products, Advanced; D008894:Milk Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D050799:STAT5 Transcription Factor; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen