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NDT Advance Access originally published online on April 23, 2007
Nephrology Dialysis Transplantation 2007 22(9):2485-2496; doi:10.1093/ndt/gfm229
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Combined effects of moderately elevated blood glucose and locally produced TGF-ß1 on glomerular morphology and renal collagen production

Søren Krag1,2, Jens R. Nyengaard2 and Lise Wogensen1

1Research Laboratory for Biochemical Pathology and 2Stereology and Electron Microscopy Research Laboratory, Aarhus University Hospital, The Institute of Clinical Medicine, The University of Aarhus, Denmark

Correspondence and offprint requests to: Søren Krag, PhD, Research Laboratory for Biochemical Pathology, Aarhus Sygehus, Noerrebrogade, 44, 8000 Aarhus C, Denmark. Email: soeren.krag{at}ki.au.dk



  Abstract

Background. There is a correlation between renal graft rejection and blood glucose (BG) levels. Furthermore, diabetic patients may develop non-diabetic renal diseases, which in some circumstances progress rapidly. Since transforming growth factor-ß1 (TGF-ß) levels are elevated in many renal diseases, the accelerated progression may be due to interactions between glucose and locally produced TGF-ß1. Therefore, we investigated the effect of mild hyperglycaemia on glomerular morphology and collagen production in TGF-ß1 transgenic mice.

Methods. To achieve BG concentrations of ~15 mmol/l in TGF-ß1 transgenic and non-transgenic mice, we used multiple streptozotocin (STZ) injections, and after 8 weeks, we measured the changes in glomerular morphology and total collagen content. We also analysed extracellular matrix (ECM) and protease mRNA levels using real-time polymerase chain reaction (PCR) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK) expression by immunohistochemistry.

Results. Mild hyperglycaemia alone had no effect on glomerular structure or ECM deposition. Over-expression of TGF-ß1 increased basement membrane thickness (BMT) and the mesangial volume fraction. Furthermore, it augmented ECM, Matrix metalloproteinase-2 (MMP), MMP-9, plasminogen activator inhibitor-1 (PAI) and tissue inhibitor of metalloproteinase-1 (TIMP) gene expression and pERK1/2 immunostaining. Elevated BG in combination with TGF-ß1 resulted in enlargement of glomerular volume, total mesangial volume and renal collagen content. Moreover, high BG exaggerated TGF-ß1-induced changes in the BMT, MMP-2 and TIMP-1 expression and pERK1/2 staining.

Conclusion. Even moderate elevations in BG accelerate the progression of those kidney diseases in which TGF-ß1 is involved. This emphasizes the importance of strict BG control in renal transplant patients and diabetic patients with renal malfunctions unrelated to diabetes.

Keywords: diabetes; fibrosis; kidney disease; non-diabetic glomerulopathy; post-transplant diabetes; TGF-ß1

Received for publication: 11. 1.06
Accepted in revised form: 23. 3.07


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