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

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-beta 1 (TGF-beta) levels are elevated in many renal diseases, the accelerated progression may be due to interactions between glucose and locally produced TGF-beta 1. Therefore, we investigated the effect of mild hyperglycaemia on glomerular morphology and collagen production in TGF-beta 1 transgenic mice. Methods. To achieve BG concentrations of similar to 15 mmol/l in TGF-beta 1 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. Overexpression of TGF-beta 1 increased basement membrane thickness (BMT) and the mesangial volume fraction. Furthermore, it augmented ECM, Matrix metalloproteinase2 (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-beta 1 resulted in enlargement of glomerular volume, total mesangial volume and renal collagen content. Moreover, high BG exaggerated TGF-beta 1-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-beta 1 is involved. This emphasizes the importance of strict BG control in renal transplant patients and diabetic patients with renal malfunctions unrelated to diabetes.