http://www.diva-portal.org/diva/getDocument?urn_nbn_se_su_diva-121-1__fulltext.pdf
Abstract
Diabetic neuropathy is believed to arise due to oxidative stress following
hyperglycemic situations. Uncoupling proteins (UCPs) constitute a subgroup
of mitochondrial transporter proteins with putative antioxidant properties. By
dissipating the proton gradient over the mitochondrial inner membrane, these
proteins reduce the mitochondrial inner membrane potential (MMP), and
thereby, the mitochondrial production of reactive oxygen species (ROS) is
decreased. In this thesis I have examined the regulation of UCP2, UCP3, and
UCP4 by the neuroprotective hormone insulin-like growth factor type 1 (IGF-
1). I have also investigated the possible involvement of UCP3 in IGF-1-
mediated neuroprotection following high glucose treatments. All studies were
performed using human neuroblastoma SH-SY5Y cells as an in vitro cell
model. The major findings were as follows:
i. Native SH-SY5Y cells expressed UCP2, UCP3, and UCP4.
ii. UCP3 was upregulated by IGF-1 via activation of the IGF-1 receptor. IGF-
1 increased UCP3 mRNA and protein levels primarily via activation of the
“classical” anti-apoptotic phosphatidyl inositol 3 (PI3)-kinase signaling
pathway, as shown by incubation with specific inhibitors of the PI3-kinase
and mitogen activated protein (MAP) kinase signaling pathways.
iii. UCP2 and UCP4 protein levels were only marginally or not at all
regulated by IGF-1. These UCPs are probably not involved in IGF-1-
mediated neuroprotection.
iv. High glucose concentrations reduced the UCP3 protein levels in highly
differentiated SH-SY5Y cells. Concomitantly, the MMP and the levels of
ROS and glutathione increased, whereas the number of neurites per cell
was reduced. This supports an antioxidant and neuroprotective role of
UCP3
v. IGF-1 prevented the glucose-induced reduction in UCP3 protein levels. In
parallel, the effects on MMP, levels of ROS and glutathione, and number
of neurites per cell were abolished or significantly reduced. These data
suggest that UCP3 is involved in IGF-1-mediated neuroprotection.
