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NDT Advance Access published online on July 30, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn399
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© The Author [2008].
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org


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

Bernd Hohenstein1, Christoph Daniel1, Birgit Hausknecht1, Kirsten Boehmer1, Regine Riess2, Kerstin U. Amann3 and Christian P. M. Hugo1

1 Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Erlangen 2 Institute of Pathology, Klinikum Nuremberg, Nuremberg 3 Institute of Pathology, University Erlangen-Nuremberg, Erlangen, Germany

Correspondence and offprint requests to: Christian Hugo, Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. Tel: +49-9131-8539002; Fax: +49-9131-8539202; E-mail: christian.hugo{at}rzmail.uni-erlangen.de



  Abstract

Background. Activation of the thrombospondin-1 (TSP-1)-TGF-β pathway by glucose and the relevance of TSP-1-dependent activation of TGF-β 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-β 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-β 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-β system as a relevant mechanism for progression of human type-2 diabetic nephropathy.

Keywords: diabetic nephropathy; proteinuria; TGF-β; TSP-1; tubulointerstitium

Received for publication: 21.10.07
Accepted in revised form: 23. 6.08


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