대한신장학회

논문분류	춘계학술대회 초록집
제목	Glycocalyx Shedding as a Novel Mechanism of Uric Acid-induced Endothelial Dysfunction
저자	Jiyeon Ko*, Eun-Sun Ryu, Dal-Ah Kim, Dong-Ryeol Ryu, Seung-Jung Kim, Kyu-Bok Choi, Duk-Hee Kang
출판정보	2016; 2016(1):
키워드	Endo-MT, Glycocalyx, HUVEC, Uric Acid
초록	Background: Recent data from experimental and clinical studies suggested a causative role of uric acid in the development and/or aggravation of cardiovascular, renal and metabolic disease. Endothelial dysfunction, which is characterized by an induction of oxidative stress and cell senescence, is regarded as one of the key mechanisms of uric acid-induced vascular and renal disease. Endothelial-to-mesenchymal transition (EndoMT) is an early and reversible process of endothelial dysfunction, and is known to play a role in the progression of renal fibrosis. Glycocalyx is a structure covering endothelium composed of membrane-bound proteoglycans and glycoproteins associated with adsorbed plasma components, which may lead to endothelial dysfunction via intraluminal shedding. Methods: EndoMT was evaluated by the changes in cell morphology and a comparison of the expression of the endothelial markers, VE-cadherin or CD31 and the mesenchymal marker, α-smooth muscle actin (α-SMA) by real time PCR, western blotting (WB) and immunocytochemistry in HUVECs and animal model of hyperuricemia (Sprague-Dawley rats fed with 2% oxonic acid for 6 weeks). NAPDH oxidase (NOX) activity, a generation of reactive oxygen species (ROS), endothelial permeability and glycocalyx shedding were investigated by WB and ELISA. To investigate the role of glycocalyx shedding in EndoMT, the effect of GM6001 (matrix metalloproteinase inhibitor) was examined in HUVECs. Results: Stimulation of HUVEC with uric acid down-regulated the expressions of CD31 and VE-cadherin with an up-regulation of α-SMA from 9 mg/dl with morphologic changes to elongated fibroblastoid cell with a loss of cell contact from 48 hours. Uric acid increased the production of ROS via NOX (15 min) and mitochondrial activation (6 hours) with an increase in glycocalyx shedding (6 hours). Uric acid-induced endoMT, glycocalyx shedding and increase in vascular permeability were blocked by probenecid (500 μM), suggesting uric acid entering into endothelial cells were responsible. Anti-oxidant treatment [N-acetylcystein (5 mM), apocynin (100 μM), and mitotempo (10 μM)] ameliorated endoMT and glycocalyx shedding in HUVEC. GM6001 (10 μM) also alleviated uric acid-induced endoMT. In the kidney of hyperuricemic rats, endothelial staining in peritubular capillaries (PTC) was significantly decreased with de-novo staining of α-SMA in PTC, which was ameliorated allopurinol treatment. Conclusion: Uric acid per se induced a phenotypic transition of endothelial cells via oxidative stress and glycocalyx shedding, which could be one of the mechanisms of uric acid-induced endothelial dysfunction and nephropathy.
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