title: Correlation of enhanced thrombospondin-1 expression, TGF-beta signalling and proteinuria in human type-2 diabetic nephropathy.
abstract: BACKGROUND
  Activation of the thrombospondin-1 (TSP-1)-TGF-beta pathway by glucose and the relevance of TSP-1-dependent activation of TGF-beta for renal matrix expansion, renal fibrosis and sclerosis have previously been demonstrated by our group in in vivo and in vitro studies. Design and methods. We investigated renal biopsies (n = 40) and clinical data (n = 30) of patients with diabetic nephropathy. Ten kidneys without evidence of renal disease served as controls. Glomerular and cortical expression of TSP-1, p-smad2/3, fibrosis and glomerular sclerosis (PAS) were assessed by immunhistochemical staining and related with clinical data.
  
  
  RESULTS
  Glomerular (g) and cortical (c) TSP-1 were increased during diabetic nephropathy (g: 2.62 +/- 2.65; c: 4.5 +/- 4.2) compared to controls (g: 0.67 +/- 0.7; c: 1.5 +/- 1.2). P-smad2/3 was significantly increased (g: 16.7 +/- 12.9; c: 148.7 +/- 92.8) compared to controls (g: 7.1 +/- 3.6; c: 55 +/- 25; P < 0.05). TSP-1 was coexpressed with p-smad2/3 as an indicator of TGF-beta activation. TSP-1 correlated with enhanced tubulointerstitial p-smad2/3 positivity (r = 0.39 and r = 0.4, P < 0.05) and glomerular p-smad2/3 correlated with proteinuria (r = 0.35, P < 0.05).
  
  
  CONCLUSIONS
  In summary, the present study suggests a functional activity of the TSP-1/TGF-beta axis, especially in the tubulointerstitium of patients with diabetic nephropathy. The positive correlation of glomerular p-smad2/3 positivity with proteinuria further supports the importance of the TSP-1/TGF-beta system as a relevant mechanism for progression of human type-2 diabetic nephropathy.
authors.affiliation: Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hohenstein
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.forename: Birgit
authors.initials: B
authors.lastname: Hausknecht
authors.forename: Kirsten
authors.initials: K
authors.lastname: Boehmer
authors.forename: Regine
authors.initials: R
authors.lastname: Riess
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Amann
authors.forename: Christian P M
authors.initials: CP
authors.lastname: Hugo
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D005355:Fibrosis; D006801:Humans; D008875:Middle Aged; D011507:Proteinuria / Q000503:physiopathology; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta