【摘 要】
：
This lecture will discuss the role of three mechanisms i.e.,poly(ADP-ribose) polymerase (PARP),12/15-1ipoxygenase (LO),and Na+/H+-exchanger-1 (NHE-1),in peripheral diabetic neuropathy (PDN).PARP catal
【机 构】
：
Mechanisms of Diabetes Complications Laboratory USA
【出 处】
：
中国上海第七届国际新药发明科技年会
论文部分内容阅读
This lecture will discuss the role of three mechanisms i.e.,poly(ADP-ribose) polymerase (PARP),12/15-1ipoxygenase (LO),and Na+/H+-exchanger-1 (NHE-1),in peripheral diabetic neuropathy (PDN).PARP catalyses conversion of nicotinamide adenine dinucleotide (NAD+) to nicotinamide and (ADP-ribose) moieties that link to nuclear and extranuclear proteins with formation ofpoly(ADP-ribose) polymers.Our studies with PARP inhibitors and PARP-deficient mice suggest that PARP activation promotes oxidative injury,inflammatory response and,ultimately,small sensory nerve fiber degeneration and axonal atrophy,associated with advanced PDN.Activation of LO leads to formation of 12-and 15-hydroxyeicosatetraenoic acids and their derivatives.These lipid products undergo spontaneous peroxidation thus contributing to oxidative stress.Our studies with LO inhibitors and LO-deficient mice implicate LO activation in functional and structural manifestations of PDN.Furthermore,LO is abundantly expressed in human Schwann cells and is involved in high glucose-induced mitogen-activated protein kinase phosphorylation.Diabetes-induced activation of the upper part of glycolysis underlies increased formation of its by-products,methylglyoxal and α-glycerophosphate,a decrease in free cytosolic NAD+/NADH ratio,NAD(P)H oxidase activation,and formation of advanced glycation end-products (AGE).We are currently testing a hypothesis that upregulation of the upper part of glycolysis results from overexpression and activation of NHE-1 and concomitant increase in intracellular pH.Our new findings with the NHE-1 inhibitor cariporide,NHE-1-deficient mice,and NHE-1 siRNA-transfected human Schwann cells support the importance of this mechanism in PDN.
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