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Ye Wang, Lixin Xie; SIRT1-responsive microRNA-182 contributes to a regulatory loop for recovery of peripheral nerve injury in experimental diabetic neuropathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4610.
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Cornea is one of the most densely innervated tissues with primarily sensory nerve fibers and corneal confocal microscopy has been used as a novel noninvasive test to diagnose and stratify the severity of human diabetic peripheral neuropathy (DPN). The corneal nerves originate from the ophthalmic branch of the trigeminal nerve. This study investigated the promotive effects and mechanism of SIRT1 on recovery of peripheral nerve injury in experimental diabetic neuropathy.
Effects of high glucose on SIRT1, microRNA-182 and NOX4 expression were assessed in primary cultures of trigeminal ganglion neurons from db/db mice by PCR and Western blotting. SIRT1 was activated by ectopic expression. Effects of miRNA-182 as a key regulational factor and targets NOX4 pathway in response to high glucose induced peripheral nerve injury were investigated in primary cultures of trigeminal ganglion neurons from db/db mice. Mechanism of SIRT1 on recovery of peripheral nerve injury were investigated in db/db mice using cornea and trigeminal ganglion as a model of peripheral nervous system.
High glucose induces down-regulation of SIRT1 and up-regulation of NOX4 in trigeminal ganglion neurons. The expression of miR-182 was also down-regulated in trigeminal ganglion neurons from db/db mice compared with wide type controls. miR-182 was found to be activated directly by SIRT1. miR-182 negatively regulate the expression of NOX4 and NOX4 is known to negatively affect nuclear SIRT1 accumulation. Direct manipulation of this miRNA pathway alters nuclear SIRT1 levels. SIRT1 enhanced neurite elongation in isolated trigeminal ganglion neurons in a dose-dependent manner. In vivo, SIRT1 injected subconjunctivally at the time of injury showed increased corneal nerve regeneration after superficial injury compared with those receiving vehicle and accelerated reinnervation. Furthermore, protein levels and the ROS-producing activity of NOX4 were also decreased in trigeminal ganglion neurons and corneas.
These results provide a valuable information of SIRT1 can accelerate the return of sensory and trophic functions of damaged peripheral nerves in DPN. In addition, this study also uncovered a mechanism of SIRT1 for the recovery of peripheral nerve injury mediated by the concerted action of miR-182 and targets NOX4 pathway that regulates SIRT1 function.
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