Oxidative and nitrosative stress play a key role in the pathogenesis of diabetic neuropathy, but the mechanisms remain unidentified. Here we provide evidence that poly(ADP-ribose) polymerase (PARP) activation, a downstream effector of oxidant-induced DNA damage, is an obligatory step in functional and metabolic changes in the diabetic nerve. PARP-deficient (PARP ؊/؊ ) mice were protected from both diabetic and galactose-induced motor and sensory nerve conduction slowing and nerve energy failure that were clearly manifest in the wild-type (PARP ؉/؉ ) diabetic or galactose-fed mice. Two structurally unrelated PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, reversed established nerve blood flow and conduction deficits and energy failure in streptozotocin-induced diabetic rats. Sciatic nerve immunohistochemistry revealed enhanced poly(ADP-ribosyl)ation in all experimental groups manifesting neuropathic changes. Poly(ADP-ribose) accumulation was localized in both endothelial and Schwann cells. Thus, the current work identifies PARP activation as an important mechanism in diabetic neuropathy and provides the first evidence for the potential therapeutic value of PARP inhibitors in this devastating complication of diabetes. Diabetes 53: 711-720, 2004 D iabetic distal symmetric sensorimotor polyneuropathy affects up to 60 -70% of diabetic patients and is the leading cause of foot ulceration and amputation (1). Improved blood glucose control reduces the risk of peripheral diabetic neuropathy (PDN), thereby implicating hyperglycemia as a leading causative factor. Diabetic hyperglycemia causes PDN via several mechanisms, among which increased aldose reductase (AR) activity (2-5), nonenzymatic glycation/glycoxidation (6,7), and activation of protein kinase C (2,8) are the best studied. All three mechanisms contribute to enhanced oxidative and nitrosative stress (4,5,7,9 -11) resulting from imbalance between production and neutralization of reactive oxygen species. Enhanced oxidative stress has been documented in peripheral nerve (4,5,8,(12)(13)(14), dorsal root and sympathetic ganglia (15), and vasculature (16,17) of the peripheral nervous system and has been implicated in neurovascular dysfunction and motor and sensory nerve conduction velocity (MNCV and SNCV) deficits, impaired neurotrophic support, nerve metabolic and signal transduction changes, and morphologic abnormalities characteristic for diabetes (4,5,12,14,16 -20). Evidence for the pathophysiologic role of reactive nitrogen species in PDN is also emerging (16,21).The question of how oxidative and nitrosative stress causes PDN remains open. We explored the role for poly(ADP-ribose) (PAR) polymerase (PARP-1; EC 2.4.2.30), a nuclear enzyme that is activated by oxidant-induced DNA single-strand breakage and transfers ADP-ribose residues from NAD ϩ to nuclear proteins (22-25). PARP-1 is present in both endothelial cells (22,23) and Schwann cells of the peripheral nerve (26). PARP-1 activation is clearly manifest in diabetes and contributes to diabetic end...
Background-We have previously shown that endothelial function is impaired not only in diabetes but also in subjects at risk of developing type 2 diabetes. We hypothesized that changes in the expression or activity of the endothelial isoform of nitric oxide synthase (eNOS), the receptor for advanced glycation end products (RAGE), and poly(ADP-ribose) polymerase (PARP) are related to this impairment. Methods and Results-We included a control group of 21 healthy subjects, a group of 22 healthy individuals with parental history of type 2 diabetes, a group of 23 subjects with impaired glucose tolerance, and a group of 21 type 2 diabetic patients. Two 2-mm forearm skin biopsies were taken from each participant and used for measurements. The percentage of PARP-positive endothelial nuclei was higher in the group with parental history of type 2 diabetes and diabetic patients compared with the controls (PϽ0.001). Immunoreactivity for nitrotyrosine (a marker of reactive nitrogen species) was higher in the diabetic group compared with all other groups (PϽ0.01). No differences in the expression of eNOS and RAGE were found among all 4 groups. The polymorphism of the eNOS gene was also studied and was not found to influence eNOS expression or microvascular functional measurements. Conclusions-PARP activation is present in healthy subjects at risk of developing diabetes as well as in established type 2 diabetic patients, and it is associated with impairments in the vascular reactivity in the skin microcirculation.
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