Combined effects of moderately elevated blood glucose and locally produced TGF-β1 on glomerular morphology and renal collagen production

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-β1 (TGF-β) levels are elevated in many renal diseases, the accelerated progression may be due to interactions between glucose and locally produced TGF-β1. Therefore, we investigated the effect of mild hyperglycaemia on glomerular morphology and collagen production in TGF-β1 transgenic mice. Methods. To achieve BG concentrations of ∼15mmol/l in TGF-β1 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-β1 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-β1 resulted in enlargement of glomerular volume, total mesangial volume and renal collagen content. Moreover, high BG exaggerated TGF-β1-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-β1 is involved. This emphasizes the importance of strict BG control in renal transplant patients and diabetic patients with renal malfunctions unrelated to diabetes. © The Author [2007].