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Hong Li, Heping Xu, Jacey Ma, Jiansu Chen, Shibo Tang; Pinacidil Rescues Diabetes-induced Down-regulation of Kir4.1 and Aquaporin-4 in Müller cells. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5377.
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Pinacidil is a ATP-depend potassium channel opener that is widely used in cardiovascular patients. This investigated the protective role of pinacidil in diabetic retinopathy with a particular emphasis on Müller cells.
Diabetes was induced in Sprague-Dawley rats by using streptozotocin (STZ). Diabetic animals were treated with pinacidil (50 mg/kg daily) intraperitoneally for 4 months, or intravitreally (3μl) once . Control diabetic rats received the same amount of vehicle. Primary Müller cells were cultured under normal glucose (NG,5 mM)for 2 weeks, high-glucose (HG,25mM)for 2 weeks, or with IL-6 (10ng/ml) or VEGF (10ng/ml) for 16h. RT-PCR, western-blot and immunohistochemistry of glial fibrillary acidic protein (GFAP), ccl2, ionized calcium binding adaptor molecule 1(Iba-1, AQP4 (aquaporin-4), kir4.1 (KCNJ10), glutaminesynthetase (GS) were investigated in rat retinas and cultured Müller cells of different groups.
The expression of GFAP, ccl2, and Iba-1 was significantly increased, whereas the expression of AQP4, kir4.1, and GS was significantly decreased at both mRNA and protein levels in diabetic retina compared with control non-diabetes retina. Treatment with pinacidil increased the expression of kir4.1 and AQP4 and decreased the expression of TNF-α, IL-1. Primary Müller cells cultured under HG condition expressed higher levels of ccl2, Iba-1,[HX1] TNF- α, IL-1β, IL-6 and lower levels of GS, kir4.1, and AQP4 compared with cells cultured under normal glucose or mannitol conditions. Cytokine IL-6 or VEGF down-regulated the expression of kir4.1 and AQP4, but up-regulated the expression of TNF- α and IL-1β in Müller cells. Pinacidil prevented HG-, or IL-6- or VEGF-induced down-regulation of kir4.1 and AQP4 in Müller cells.
Our results suggest that pinacidil can suppress Müller cell activation and improve K+ channel and water channel expression in diabetes or inflammatory conditions. Pinacidil may have therapeutic effect in diabetic retinopathy.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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