Thompson, KaylaChen, JonathanLuo, QianyiXiao, YuchengCummins, Theodore R.Bhatwadekar, Ashay D.2018-06-142018-06-142018-02-23Thompson, K., Chen, J., Luo, Q., Xiao, Y., Cummins, T. R., & Bhatwadekar, A. D. (2018). Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Müller cells. PLoS ONE, 13(2). https://doi.org/10.1371/journal.pone.01932801932-6203https://hdl.handle.net/1805/16510Diabetic 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.en-USAttribution 3.0 United StatesDiabetic retinopathyblindnessMüller cell dysfunctionArticle