Brezniceanu M-L, Liu F, Wei C-C, Tran S, Sachetelli S, Zhang S-L, Guo D-F, Filep J G, Ingelfinger J R, Chan J S D
Research Centre, Centre hospitalier de l'Université de Montréal (CHUM)-Hôtel-Dieu, Montreal, Quebec, Canada.
Kidney Int. 2007 May;71(9):912-23. doi: 10.1038/sj.ki.5002188. Epub 2007 Mar 7.
Increased generation of reactive oxygen species (ROS) leads to oxidative stress in diabetes. Catalase is a highly conserved heme-containing protein that reduces hydrogen peroxide to water and oxygen and is an important factor decreasing cellular injury owing to oxidative stress. Hyperglycemic conditions increase oxidative stress and angiotensinogen gene expression. Angiotensinogen conversion to angiotensin II leads to a furtherance in oxidative stress through increased generation of reactive oxygen species. In this study, we utilized mice transgenically overexpressing rat catalase in a kidney-specific manner to determine the impact on ROS, angiotensinogen and apoptotic gene expression in proximal tubule cells of diabetic animals. Proximal tubules isolated from wild-type and transgenic animals without or with streptozotocin-induced diabetes were incubated in low glucose media in the absence or presence of angiotensin II or in a high-glucose media. Our results show that the overexpression of catalase prevents the stimulation of ROS and angiotensinogen mRNA in tubules owing to elevated glucose or angiotensin II in vitro. Additionally, overexpression of catalase attenuated ROS generation, angiotensinogen and proapoptotic gene expression and apoptosis in the kidneys of diabetic mice in vivo. Our studies point to an important role of ROS in the pathophysiology of diabetic nephropathy.
活性氧（ROS）生成增加会导致糖尿病中的氧化应激。过氧化氢酶是一种高度保守的含血红素蛋白，可将过氧化氢还原为水和氧气，是减少氧化应激引起的细胞损伤的重要因素。高血糖状况会增加氧化应激和血管紧张素原基因表达。血管紧张素原转化为血管紧张素II会通过增加活性氧的生成进一步加重氧化应激。在本研究中，我们利用以肾脏特异性方式转基因过表达大鼠过氧化氢酶的小鼠，来确定其对糖尿病动物近端小管细胞中ROS、血管紧张素原和凋亡基因表达的影响。从野生型和转基因动物中分离出的近端小管，在未患或患有链脲佐菌素诱导糖尿病的情况下，于低葡萄糖培养基中在不存在或存在血管紧张素II的情况下孵育，或在高葡萄糖培养基中孵育。我们的结果表明，过氧化氢酶的过表达可防止体外因葡萄糖或血管紧张素II升高而对小管中ROS和血管紧张素原mRNA的刺激。此外，过氧化氢酶的过表达可减轻体内糖尿病小鼠肾脏中的ROS生成、血管紧张素原和促凋亡基因表达以及细胞凋亡。我们的研究指出了ROS在糖尿病肾病病理生理学中的重要作用。
