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Wennan Lu, Jean Sévigny, Gulab S Zode, Val Sheffield, Alan M Laties, Claire H Mitchell; Sustained rise in extracellular ATP in retina of transgenic Tg-MYOCY437H mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1345.
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Retinal neurons and astrocytes response to short-term mechanical strain by releasing ATP. As most glaucoma patients experience sustained strains accompanying a prolonged elevation of intraocular pressure (IOP), we asked whether ATP released was also sustained. The chronic moderate elevation of IOP in the Tg-MYOCY437Hmouse made it an ideal model for asking if extracellular ATP levels were sustained with prolonged IOP elevation.
IOP from littermate C56BL/6N and Tg-MYOCY437Hmice was measured monthly using a TonoLab tonometer. Retinal ganglion cell (RGC) counts in selected regions were performed after labeling retinal whole mounts with the Brn-3a antibody. The expression of NTPDase1 was compared at the mRNA level using qPCR and at protein level using standard Western blot techniques.
The IOP increased steadily from 10-40 weeks in transgenic Tg-MYOCY437H mice as compared to wild-type sibling controls. At 40 weeks, the IOP in the transgenic mice was significantly higher than in controls, at 15.64 ±0.26 vs. 12.14±0.15. Brn-3b staining showed a 25.2% drop in RGC number in the peripheral region and a 12.9% drop in RGCs the middle region of 40 week old Tg-MYOCY437H mice as compared to controls, but not the central region. RGC numbers did not differ across superior, inferior, nasal and temporal quadrants. mRNA for NTPDase1 was significantly increased in retinas from 40 week old Tg-MYOCY437H mice as compared to control, with gene levels correlated with IOP. NTPDase1 was also elevated at the protein level in Tg-MYOCY437H mice.
The loss of RGCs in the periphery of Tg-MYOCY437H mice supports a glaucomatous damage due to the IOP elevation. The elevation of the extracellular ATP marker NTPDase1 at both mRNA and protein level suggest elevated IOP increases ATP release in mice as it does in rats, primate and humans. Importantly, these results suggest that perturbed ATP signaling is sustained in chronic glaucoma.
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