Diabetic nephropathy is a major complication of diabetes leading to end-stage renal disease, which requires hemodialysis. Although the mechanism by which it progresses is largely unknown, the role of hyperglycemia-derived oxidative stress has recently been the focus of attention as the cause of diabetic complications. Constituent cells of the renal glomeruli have the capacity to release reactive oxygen species (ROS) upon stimulation of NADPH oxidase activated by protein kinase C (PKC).Hyperglycemia and insulin resistance in the diabetic state are often associated with activation of PKC and tumor necrosis factor (TNF)-α, respectively. The aim of this study is to clarify the signaling pathway leading to ROS production by PKC and TNF-α in rat glomeruli. Isolated rat glomeruli were stimulated with phorbol 12-myristate 13-acetate (PMA) and TNF-α, and the amount of ROS was measured using a chemiluminescence method. Stimulation with PMA (10 ng/ml) generated ROS with a peak value of 136±1.2 cpm/mg·protein (mean±SEM). The PKC inhibitor H-7, the NADPH oxidase inhibitor diphenylene iodonium and the phosphatidylinositol-3 (PI-3) kinase inhibitor wortmannin inhibited PMA-induced ROS production by 100%, 100% and 80%, respectively. In addition, TNF-α stimulated ROS production (283±5.8/mg·protein/20 min).The phosphodiesterase inhibitor cilostazol activates protein kinase A and is reported to improve albuminuria in diabetic rats. Cilostazol (100 μg/ml) inhibited PMA, and TNF-α-induced ROS production by 78±1.8, and 19±2.7%, respectively. The effects of cilostazol were not additive with wortmannin. Cilostazol arrests oxidative stress induced by PKC activation by inhibiting the PI-3 kinase-dependent pathway, and may thus prevent the development of diabetic nephropathy.

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This paper presents design consideration, machine architecture, and parallel programming environment for the parallel machine Cenju-3, the first MPP product of NEC. Cenju-3 utilized fast commodity RISC microprocessors, VR44OOs in a distributed sharedmemory arrangement and can be configured up to 256 processing elements, connected through a multistage inter-connection network. It results a compact and scalable parallel machine, with operating speeds ranging from 256 MFLOPS to a maximum of 12.8GFLOPS. A hardware support for the interprocessor communication realizes efficient message/ data transmissions among processors.Also, a programming environment, PCASE has being developed, an order to fully utilize the Cenju-3. PCASE translates a sequential user program into its eficient parallel form with minimum user interventions.Preliminary results and future direction are also described.

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