title: TGF-beta type II receptor deficiency prevents renal injury via decrease in ERK activity in crescentic glomerulonephritis.
abstract: The role of transforming growth factor-beta (TGF-beta) receptor complex in the pathogenesis of crescentic glomerulonephritis (GN) is not clear. To test the hypothesis that TGF-beta signaling plays a crucial role in the development and progression of crescentic GN by inducing the activation of extracellular signal-regulated kinase (ERK) and expression of its target genes, anti-glomerular basement membrane (GBM) GN was induced in TGF-beta type II receptor (TGF-betaIIR) gene heterozygous (TGF-betaIIR(+/-)) C57BL/6J mice and wild-type animals. GN was initiated in preimmunized mice by administration of rabbit anti-mouse GBM serum. TGF-betaIIR deficiency was significantly associated with decreased renal damage at days 14, 21, and 28 after induction of GN: renal function impairment, proteinuria, proportion of crescents, glomerular accumulation of periodic acid-Schiff-positive material, relative cortical interstitial volume, as well as renal cortical phosphorylation of ERK and plasminogen activator inhibitor type I (PAI-1) and alpha2(I) collagen mRNA levels were significantly decreased in TGF-betaIIR(+/-) mice compared with wild-type animals. These results provide the first direct evidence that TGF-betaIIR deficiency protects against renal injury in crescentic GN, possibly by inhibiting the sustained activation of ERK and PAI-1 and alpha2(I) collagen gene expression. Thus, TGF-beta signaling appears to play an important role in the development and progression of crescentic GN by inducing the ERK activity, and PAI-1 and alpha2(I) mRNA expression.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea.
authors.forename: C Y
authors.initials: CY
authors.lastname: Song
authors.forename: B C
authors.initials: BC
authors.lastname: Kim
authors.forename: H K
authors.initials: HK
authors.lastname: Hong
authors.forename: H S
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D002196:Capillaries / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics; D003404:Creatinine / Q000097:blood; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050533:Glomerular Basement Membrane / Q000276:immunology; D005921:Glomerulonephritis / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology*; D007672:Kidney Cortex / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011507:Proteinuria; D012333:RNA, Messenger / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics; D012079:Renal Circulation
chemical_list: D024042:Collagen Type I; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D003404:Creatinine; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II