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Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Müller cells.

Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Müller cells.
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Thompson K, Chen J, Luo Q, Xiao Y, Cummins TR, Bhatwadekar AD,


Thompson K, Chen J, Luo Q, Xiao Y, Cummins TR, Bhatwadekar AD, (click to view)

Thompson K, Chen J, Luo Q, Xiao Y, Cummins TR, Bhatwadekar AD,

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PloS one 2018 02 2313(2) e0193280 doi 10.1371/journal.pone.0193280
Abstract

Diabetic retinopathy (DR) is a major cause of adult blindness. Retinal Müller cells maintain water homeostasis and potassium concentration via inwardly rectifying Kir4.1 channels. Accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. While diabetes leads to a decrease in the Kir4.1 channels, it remains unknown whether AGEs-linked to the basement membrane (BM) affect normal Kir4.1 channels. For this study, we hypothesized that AGE-modification of laminin is detrimental to Kir4.1 channels, therefore, disrupting Müller cell function. The AGE-modified laminin-coated substrates were prepared by incubating Petri-dishes with laminin and methylglyoxal for seven days. The rat Müller cells (rMC-1) were propagated on AGE-modified laminin, and Kir4.1 expression and function were evaluated. Quantification of AGEs using ELISA revealed a dose-dependent increase in methylglyoxal-hydro-imidazolone adducts. The rMC-1 propagated on AGE-modified laminin demonstrated a decrease in Kir4.1 levels in immunofluorescence and western blot studies and a decrease in the Kir4.1 channel function. Kir4.1 decrease on AGE-modified laminin resulted in a disorganization of an actin cytoskeleton and disruption of α-dystroglycan-syntrophin-dystrophin complexes. Our studies suggest that AGE-modification of laminin is detrimental to Kir4.1 channels. By studying the role of AGEs in Kir4.1 channels we have identified a novel mechanism of Müller cell dysfunction and its subsequent involvement in DR.

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