Insulin-like growth factor-1 mediated protection against hyperglycemia-induced reactive oxygen species in renal and neuronal cell models

Diabetes, caused by insulin deficiency/resistance, has multiple complications, including nephropathy and neuropathy. Highly active antiretroviral therapy for human immunodeficiency virus (HIV) disease also causes type 2 diabetes. HIV-associated dementia (HAD) is a central nervous system (CNS) disorder in HIV-patients. Hyperglycemia and HIV-induced tumor necrosis factor-alpha (TNFalpha) may work together to cause neurodegeneration.;Hyperglycemia-induced reactive oxygen species (ROS) cause (renal) mesangial and neuronal cell apoptosis. In mesangial cells, I have verified that insulin-like growth factor-1 (IGF-1) mediated protection from high glucose (HG)-induced damage through ROS reduction, DNA damage attenuation and facilitation of homologous recombination-directed repair (HRR) of DNA double strand break. Furthermore, IGF-1 promotes Rad51, a key enzyme of HRR, recruiting to damaged DNA foci. In neurons, I have demonstrated that IGF-1 attenuates HG-induced ROS accumulation, loss of neuronal processes and apoptosis. IGF-1 also reduces both HG and TNFalpha mediated ROS accumulation and apoptosis.;The redox and pro-apoptotic function of p66Shc, an adaptor associated with cell aging/death and transcription factor FOXO3a, have been investigated under HG. I have shown that silencing wild type (WT) p66Shc with mutant of p66Shc or with siRNA against p66Shc reduces HG-induced ROS accumulation. This p66Shc inhibition on 36-Ser residue in mesangial cells also reduces HG-induced ROS-dependent phosphorylation of Akt and FOXO3a, known to facilitate FOXO3a nuclear localization and FOXO3a transcriptional activation of superoxide dismutase (SOD). In neurons, IGF-1 increases FOXO3a nuclear presence under HG, attenuating HG-induced ROS accumulation. Moreover, it has initially been demonstrated that FOXO3a activity may be associated with SOD expression in human CNS with HIV-encephalopathy. In my models, I have firstly demonstrated that WTp66Shc is critical for oxidative stress and DNA damage/apoptosis.;I have primarily proven that IGF-1 attenuation of HG-induced ROS accumulation might be dependent on WTp66Shc.;Furthermore, I have pointed to the transition of TNFalpha neuroprotective and neurotoxic dual functions in neurons by testing shifting point of ROS accumulation.;Both IGF-1 treatment and down-regulation of WTp66shc function could offer potential therapeutic strategy against renal/neuronal injuries associated with the impaired glucose metabolism. Further investigation of the transition of TNFalpha dual functions may lead to identification of potential therapeutic strategy for HAD.