title: Heterozygous mice for TGF-betaIIR gene are resistant to the progression of streptozotocin-induced diabetic nephropathy.
abstract: BACKGROUND
  Transforming growth factor-beta (TGF-beta) receptor complex and its downstream Smad signaling intermediates constitute an extracellular matrix (ECM) accumulation pathway.
  
  
  METHODS
  In the present study, we examined whether decreased expression of the TGF-beta type II receptor (TGF-betaIIR) in TGF-betaIIR gene heterozygous (TGF-betaIIR+/-) (HT) mice could inhibit the Smad signaling pathway and subsequent progression of renal lesions when streptozotocin (STZ) diabetes is induced.
  
  
  RESULTS
  At the end of the 28-week experiment after STZ injections, wild-type diabetic mice showed severe glomerular hypertrophy and mesangial matrix accumulation occasionally featuring nodular glomerulosclerosis. In contrast, mean glomerular area and mesangial volume density were significantly decreased in the HT diabetic mice as compared with the wild-type diabetic mice. Immunostaining for phosphorylated Smad2/Smad3 and TGF-betaIIR in the glomerular cells was also significantly reduced in the HT diabetic mice. Southwestern histochemistry using digoxigenin-labeled CAGA sequence probes showed that localization of labeled probes to the nuclei of glomerular cells in the HT diabetic mice was significantly less frequent than that in the wild-type diabetic animals. Northern blot analysis showed that alpha1(IV) collagen mRNA levels were significantly reduced in the kidney tissue of HT diabetic mice as compared with the wild-type diabetic mice.
  
  
  CONCLUSIONS
  These results suggest that decreased expression of TGF-betaIIR in the HT diabetic mice can inhibit the progression of diabetic renal injury by inhibiting the downstream Smad signaling pathway and subsequent ECM gene expression. Thus, TGF-betaIIR appears to play an important role in the progression of diabetic nephropathy by mediating intracellular Smad signaling.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hwal Woong
authors.initials: HW
authors.lastname: Kim
authors.forename: Bong Cho
authors.initials: BC
authors.lastname: Kim
authors.forename: Chi Young
authors.initials: CY
authors.lastname: Song
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Hye Kyoung
authors.initials: HK
authors.lastname: Hong
authors.forename: Hyun Soon
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D004268:DNA-Binding Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005920:Glomerular Mesangium / Q000473:pathology; D006579:Heterozygote; D006651:Histocytochemistry; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II