An impact of HSP genes as new therapeutic target moleculesf or diabetic neplunpathy

为了探索与糖尿病肾病发展有关的新的治疗靶点分子，我们利用DNA微阵列技术建立了糖尿病肾脏基因表达谱的时间过程数据。随着时间的推移，2型糖尿病模型小鼠（db/db）肾脏中热休克蛋白（HSP）、应激反应性伴侣蛋白的基因表达受到抑制，与对照小鼠（db/m nice）相比。db/db小鼠肾脏中HSP70蛋白水平仅在糖尿病早期升高，随后下降。在培养的系膜细胞中，高糖培养基诱导HSP70表达，氧化应激抑制HSP70 mRNA和蛋白水平。在组成性过表达HSP70的系膜细胞中，氧化应激诱导的细胞凋亡被阻止。具有肾保护作用的促红细胞生成素诱导HSP70在肾细胞和肾脏中的表达。这些结果表明，在2型糖尿病模型小鼠肾脏中，HSP70的表达在高血糖时先升高，然后在慢性糖尿病加重的氧化应激下降低。因此，HSP70抗氧化应激防御机制的失效可能参与了糖尿病肾病的发生发展，诱导HSP70可能是预防糖尿病肾病的一种手段

To explore new therapeutic target molecules which involve in the development of diabetic nephropathy, we created a time course data of gene expression profiles in the diabetic kidney by a DNA microarray method. Gene expression of the genes which belonged to Heat Shock Protein (HSP), stress responsiveness chaperonin, was inhibited in the kidney of the type 2 diabetic model mice, db/db mice, in comparison to the control mice, db/m nice, over the time-course. The protein levels of HSP70 were increased in the kidney from db/db mice only at the early course of diabetes and were then decreased. In cultured mesengial cells, high glucose medium induced the HSP70 expression, whereas oxidative stress inhibited the mRNA levels and protein levels of HSP70. In the mesangial cells which were constitutively over-expressed HSP70, oxidative stress-induced apoptosis was prevented. Erythropoietin which has a reno-protective effect was induced HSP70 expression in the renal cells and the kidney. These results suggest that, in the kidney of type 2 diabetic model mice, HSP70 expression first increases in response to hyperglycemia and then decreases due to oxidative stress enhanced by chronic diabetic condition. Thus, the failure of the anti-oxidative stress defense mechanism of HSP70 may involve in the development of diabetic nephropathy and an induction of HSP70 might be a tool to prevent diabetic nephropathy