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Qianyi Luo, Kayla Thompson, Ashay D Bhatwadekar; The insulin receptor substrate-1 (IRS-1) regulates Kir4.1 expression in retinal Müller cells. Invest. Ophthalmol. Vis. Sci. 2017;58(8):804.
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© ARVO (1962-2015); The Authors (2016-present)
The Müller cells, principal glia of the retina, maintain water homeostasis and K+ concentration via the specialized inwardly rectifying K+ (Kir) channels. Diabetes leads to a decrease in Kir4.1 expression. Our studies suggest that the diurnal rhythm of Kir4.1 is dampened in diabetes. The insulin receptor substrate-1 (IRS-1) is a critical regulator of insulin signaling in Müller cells, however, the potential role of signaling mediated by IRS-1 in regulating the Kir4.1 expression remains unknown.
To determine the importance of insulin in Kir4.1 regulation, the rat Müller (rMC-1) cells were treated with insulin and Kir4.1 expression was examined by western blot. To evaluate the role of IRS-1 in Kir4.1 regulation, the rMC-1 cells were treated with an IRS-1 inhibitor Sectin-H3. In parallel, the type 2 diabetic mice (db/db) mice maintained under a regular light-dark condition or a constant dark (circadian dysrhythmia) were euthanized at different time intervals and the retinal expression of IRS-1 was determined using western blot.
The treatment of rMC-1 cells with insulin resulted in an increase in Kir4.1 expression. The pharmacological inhibition of IRS-1 with Secin-H3 resulted in a 1.5-fold decrease in a Kcnj10 expression (gene for Kir4.1). The IRS-1 exhibited a diurnal rhythm with a peak increase at 4 am and at the lowest levels at 4 pm. The circadian dysrhythmia led to a loss of diurnal rhythm Kir4.1 along with a change in the characteristic pattern of IRS-1 rhythm.
Our studies suggest that IRS-1 is a critical regulator of Kir4.1 expression in retinal Müller cells. In diabetes, the dysfunctional signaling mediated by IRS-1 is detrimental to Kir4.1 expression.
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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