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

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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