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Bruce A Berkowitz, Xiangyi Wen, Wallace B Thoreson, Timothy S Kern, Robin Roberts; Abnormal rod calcium homeostasis and the development of retinal oxidative stress in diabetes. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4280.
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© ARVO (1962-2015); The Authors (2016-present)
To test the hypothesis that rod-dominated retinal oxidative stress in diabetes (PMID: 2406764) arises from dysregulation of rod photoreceptor cells calcium homeostasis leading to supernormal cytosolic calcium content, an important trigger for mitochondrial and / or NADPH oxidase superoxide production.
Non-diabetic (wt) and 2 mo diabetic C57Bl6/J mice were studied with manganese-enhanced MRI (MEMRI), optical calcium imaging with Fura2, and superoxide production assays. BAY K 8644 (L-type calcium channel (LTCC) agonist), or 2,4,6-PYT (selective Cav1.3 antagonist, kind gift from Dr. Richard Silverman, NWU) treatments were investigated.
Diabetes impairs retinal calcium ATPase activity (PMID: 8206713). We thus hypothesized suppressed calcium efflux via plasma membrane calcium ATPase, and impaired store-filling via sarcolemma calcium ATPase with engagement of calcium entry into rods through non-LTCCs. Our new MEMRI data in dark adaptation diabetic mice treated with BAY K 8644 supported this hypothesis. This model predicts that rod calcium content would be supernormal. Initial studies in dark adapted diabetic mice rods verified this prediction. Further, in non-diabetic dark adapted mice, four hours post selective pharmacologic closing of Cav1.3 LTCCs reproduced the paradoxical MEMRI pattern observed in diabetic mice, and resulted in supernormal superoxide free radical production, suggesting that prolonged closure of Cav1.3 LTCCs is upstream of impaired rod calcium ATPase activity.
Collectively, these new data suggest that abnormal calcium homeostasis and Cav1.3 LTCCs closure in particular, contribute to the oxidative stress in early diabetic retinopathy.
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