Krag Søren, Nyengaard Jens R, Wogensen Lise
Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus C, Denmark.
Nephrol Dial Transplant. 2007 Sep;22(9):2485-96. doi: 10.1093/ndt/gfm229. Epub 2007 Apr 23.
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-beta1 (TGF-beta) levels are elevated in many renal diseases, the accelerated progression may be due to interactions between glucose and locally produced TGF-beta1. Therefore, we investigated the effect of mild hyperglycaemia on glomerular morphology and collagen production in TGF-beta1 transgenic mice.
To achieve BG concentrations of approximately 15 mmol/l in TGF-beta1 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.
Mild hyperglycaemia alone had no effect on glomerular structure or ECM deposition. Over-expression of TGF-beta1 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-beta1 resulted in enlargement of glomerular volume, total mesangial volume and renal collagen content. Moreover, high BG exaggerated TGF-beta1-induced changes in the BMT, MMP-2 and TIMP-1 expression and pERK1/2 staining.
Even moderate elevations in BG accelerate the progression of those kidney diseases in which TGF-beta1 is involved. This emphasizes the importance of strict BG control in renal transplant patients and diabetic patients with renal malfunctions unrelated to diabetes.
肾移植排斥反应与血糖(BG)水平之间存在关联。此外,糖尿病患者可能会发展为非糖尿病性肾脏疾病,在某些情况下,这些疾病进展迅速。由于许多肾脏疾病中转化生长因子-β1(TGF-β)水平升高,疾病加速进展可能是由于葡萄糖与局部产生的TGF-β1之间的相互作用。因此,我们研究了轻度高血糖对TGF-β1转基因小鼠肾小球形态和胶原蛋白产生的影响。
为使TGF-β1转基因和非转基因小鼠的BG浓度达到约15 mmol/l,我们多次注射链脲佐菌素(STZ),8周后,测量肾小球形态和总胶原蛋白含量的变化。我们还使用实时聚合酶链反应(PCR)分析细胞外基质(ECM)和蛋白酶mRNA水平,并通过免疫组织化学分析磷酸化细胞外信号调节激酶1/2(pERK)的表达。
单独的轻度高血糖对肾小球结构或ECM沉积没有影响。TGF-β1的过度表达增加了基底膜厚度(BMT)和系膜体积分数。此外,它增强了ECM、基质金属蛋白酶-2(MMP)、MMP-9、纤溶酶原激活物抑制剂-1(PAI)和金属蛋白酶组织抑制剂-1(TIMP)基因表达以及pERK1/2免疫染色。BG升高与TGF-β1共同作用导致肾小球体积、总系膜体积和肾脏胶原蛋白含量增大。此外,高BG加剧了TGF-β1诱导的BMT、MMP-2和TIMP-1表达以及pERK1/2染色的变化。
即使是中度BG升高也会加速那些涉及TGF-β1的肾脏疾病的进展。这强调了严格控制BG对肾移植患者和患有与糖尿病无关的肾功能障碍的糖尿病患者的重要性。