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Ji-yeon Do, In kyu Lee, Dong Ho Park; New role of pyruvate dehydrogenase kinase 4 in retinal ganglion cell death after Ischemia/reperfusion injury. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2563.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the involvement of pyruvate dehydrogenase kinase 4 (PDK4), the regulatory enzyme in glycolytic pathway, on ischemia/reperfusion injured retinal ganglion cells (RGCs).
To induced I/R injury in C57BL/6J wild-type (WT) and PDK4 knock-out (K/O) mice, the anterior chamber of the right eye was cannulated with a 30-gauge needle connected to a saline reservoir at 150 cm above the eye, leading to a high IOP of 110 mm Hg for 1h. In Sprague-Dawley (SD) rats, retinal I/R injury was induced by elevating the IOP to 120 mm Hg for 1h. Expression of PDK4 was measured by Western blot, real-time PCR analysis. To determined the effect of PDK4 on RGC loss by I/R injury, immunofluorescence (IF) staining was performed with RGC marker at 7 days after injury.To confirmed the effect of PDK inhibition in vitro, RGC-5 cells were changed to serum/glucose-free medium and deprived of oxygen (1 percent of oxygen) using an anaerobic chamber for 6 h with and without dichloroacetate (DCA) treatment. Western blot analysis was performed to investigate whether apoptosis protein expression regulated by DCA treatment.
In WT mice and SD rat, retinal PDK4 expression was increased in I/R-injured eyes compared to uninjured eyes. I/R injury induced RGC loss and decreased thickness of retina in both WT and PDK4 K/O mice. However, in PDK4 K/O mice retina, loss of RGC were lower than those of WT. DCA, a synthetic PDK inhibitor, decreased expression of apoptosis protein induced by oxygen and glucose deprivation (OGD) in RGC-5 cells.
These findings suggest that PDK4 expression and activity related to RGC loss after I/R injury. Therefore, inhibition of PDK4 activity might be a therapeutic target for I/R-induced disease such as glaucoma.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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