Molecular Mechanism in the development of diabetic nephropathy-the role of diacylglycerol kinase in regulating protein kinase C activity-

糖尿病肾病是西方和亚洲社会终末期肾病的主要原因。高血压是糖尿病肾病发展的最重要的单一危险因素。我们以前的研究表明，PKC抑制剂治疗不仅可以改善肾小球功能障碍的早期变化，如肾小球高滤过和蛋白尿增加，而且可以使糖尿病动物中TGF-β1和细胞外基质成分的mRNA表达增加和系膜扩张正常化。因此，我们一直认为肾小球PKC激活在糖尿病肾病的发展中起着关键作用。因此，我们试图阐明糖尿病PKC激活的调节机制。我们关注的是二酰基甘油激酶的活性，因为众所周知，它通过二酰基甘油代谢减弱PKC活性。在这项研究中，我们检测了维生素E、曲格列酮和吡格列酮的作用，这些药物可以抑制糖尿病。 ...更多信息 阿比特斯诱导的肾小球PKC激活，调节甘油二酯激酶的活性。此外，我们测量了肾小球系膜细胞对H2 O2的二酰基甘油激酶活性，因为从糖尿病大鼠分离的肾小球表现出DCF估计的氧化应激。我们还尝试用退化PCR方法克隆肾脏特异性甘油二酯激酶。噻唑烷二酮类药物如曲格列酮和吡格列酮通过增强甘油二酯活性抑制糖尿病诱导的PKC激活，类似于维生素E。H_2O_2对肾小球系膜细胞甘油二酯活性有剂量依赖性的抑制作用。我们发现从大鼠肾脏中克隆的甘油二酯激酶与大鼠甘油二酯激酶α相似。总之，糖尿病诱导的肾小球PKC激活可以通过增强二酰甘油活性，通过抗氧化剂，如噻唑烷二酮类和维生素E调制，从而表明抗氧化剂可能是糖尿病肾病的一个重要的治疗策略。少

Diabetic nephropathy is the leading cause of end-stage renal disease in Western as well as Asian society. Hyperglycemia is the single most important risk factor for the development of diabetic nephropathy. We have previously shown that the treatment with PKC inhibitor ameliorated not only early changes of glomerular dysfunction such as glomerular hyperfiltration and increased albuminuria, but also normalized the increase in mRNA expression of TGF-β1 and extracellular matrix components and mesangial expansion in diabetic animals. Thus, we have been suggesting the pivotal role of glomerular PKC activation in the development of diabetic kidney disease. Thus, we tried to clarify the mechanism by which diabetes-PKC activation could be regulated. We focused on the activity of diacylglycerol kinase, since which is well known to attenuate PKC activity through diacylglycerol metabolism. In this study, we have examined the effect of vitamin E, troglitazone, and pioglitazone, which can inhibit di … More abetes-induced glomerular PKC activation, in regulating activity of diacylglycerol kinase. In addition, we measured diacylglycerol kinase activity of mesangial cells in response to H202 because the glomeruliisolated from diabetic rats exhibited oxidative stress estimated by DCF. We also tried to clone kidney-specific diacylglycerol kinase with degenerative PCR method. Thiazolidinediones such as troglitazone and pioglitazone inhibited diabetes-induced PKC activation via enhancement of diacylglycerol activity similar to vitamin E. Exposing mesangial cells to H2O2 inhibited diacylglycerol activity in its dose-dependent manner. We found that cloned diacylglycerol kinase from rat kidney was similar to rat diacylglycerol kinase α. In conclusion, diabetes-induced glomerular PKC activation could be modulated by enhancing diacylglycerol activity via antioxidants such as thiazolidinediones and vitamin E, thus suggesting that antioxidants could be a crucial therapeutic strategy for diabetic kidney disease. Less