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. 2008 Dec;23(12):3880-7.
doi: 10.1093/ndt/gfn399. Epub 2008 Jul 30.

Correlation of enhanced thrombospondin-1 expression, TGF-beta signalling and proteinuria in human type-2 diabetic nephropathy

Bernd Hohenstein  1 , Christoph Daniel, Birgit Hausknecht, Kirsten Boehmer, Regine Riess, Kerstin U Amann, Christian P M Hugo
Affiliations

Correlation of enhanced thrombospondin-1 expression, TGF-beta signalling and proteinuria in human type-2 diabetic nephropathy

Bernd Hohenstein et al. Nephrol Dial Transplant. 2008 Dec.

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.

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Figures

Fig. 1
Fig. 1
TSP-1 expression is enhanced during type-2 diabetic nephropathy. Immunohistochemistry of TSP-1 in normal kidneys demonstrated the wide absence of TSP-1 in glomeruli (A) but some low level TSP-1 in tubules (B). Glomerular (C) and cortical (D; representing mainly tubulointerstitial) TSP-1 expression were evaluated as described in the Material and methods section and were increased in type-2 diabetic nephropathy. Expression levels of glomerular (E) and cortical (F) TSP-1 varied among biopsies with different severity of lesions. With ongoing disease (G) TSP-1 expression within glomeruli could be detected in various glomerular and inflammatory cells (H, I). In the tubulointerstitium, TSP-1 was mainly confined to tubules and inflammatory interstitial cells (G, H). Kimmelstiel–Wilson lesions demonstrated a typical staining pattern (J) (*P < 0.05 by the Mann–Whitney U-test).
Fig. 2
Fig. 2
Increased TGF-β expression and p-smad2/3 positivity during advanced diabetic nephropathy. Glomerular (A) and tubulointerstitial (B) immunohistochemistry of TGF-β-1/2 were evaluated using a semiquantitative scoring system as described in the Material and methods section. Immunohistochemistry of p-smad2/3 was evaluated by counting positive cells in glomeruli and the tubulointerstitium. Glomerular p-smad2/3 was increased in all diabetic biopsies (C) and biopsies with mild (grade 1) and advanced (grade 3) lesions (D) whereas cortical p-smad2/3 was increased in all subgroups (E, F). Double labelling of TSP-1 and p-smad2/3 was performed as described in the Material and methods section (G, H). Panel G and its zoomed areas depict glomerular co-localization; panel H depicts the clear co-localized TSP-1 and p-smad 2/3 in the tubulointerstitium of diabetic kidneys (*P < 0.05 by the Mann–Whitney U-test; #P < 0.05 by the unpaired t-test and Welch-test).
Fig. 3
Fig. 3
TSP-1 expression and p-smad2/3 positivity correlate in the tubulointerstitium. Correlations were calculated using Spearman's algorithm. Thereby, cortical TSP-1 (A) and glomerular TSP-1 (B) correlated with p-smad2/3 positivity in the tubulointerstitium. The number of glomerular cells positive for p-smad2/3 also correlated with proteinuria in patients with diabetic nephropathy (C).
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