Elevated Glucose Impairs Endothelial Kir2.1 Channel Function and Degrades the Glycocalyx<i>in vitro</i>

Insulin resistance and hyperglycemia are associated with endothelial dysfunctionthough the mechanisms are not well understood. Endothelial dysfunction ischaracterized by an impairment of endothelial-dependent control of vascular tone withmajor contributions from the inwardly rectifying potassium channel Kir2.1. Kir2.1function is dependent on the glycocalyx, an extracellular matrix composed ofproteoglycans (PGs) and glycosaminoglycans (GAGs) previously shown to be grosslydisrupted in obesity and diabetes. In this study, we determined the effects of treatingendothelial cells with prolonged exposures to elevated glucose (i.e., 200 mg/dL for 72hours) using whole-cell patch clamp electrophysiology to study Kir2.1 function. We nexttested the presence and expression of specific glycocalyx GAGs and PGs usingimmunocytochemistry and Western blotting. Our work reveals that endothelial cellsexposed to elevated glucose exhibit reduced Kir2.1 function and reduced presence orexpression of specific glycocalyx components, namely heparan sulfate GAGs andsyndecan-1 PG. Similar findings were observed when cells were treated with mannitol, however the biologically inactive L-glucose had no effect. Furthermore, Kir2.1impairment appears to be independent of osmotic stress as assessed by challengingcells with elevated NaCl. As neither glucose nor mannitol influenced Kir2.1 expression, we infer that alterations to the glycocalyx may underly channel dysfunction in thepresence of these monosaccharides. Ongoing work in our lab aims to determine ifrestoring heparan sulfate or syndecan-1 expression will rescue Kir2.1 function in thepresence of increased sugars. Institutional Development Award (IDeA) from National Institute of General Medical Sciences Grant 2P20GM113125. University of Delaware Research Funds This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.