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Hyperuricemia enhances intracellular urate accumulation via down-regulation of cell-surface BCRP/ABCG2 expression in vascular endothelial cells.
Biochim Biophys Acta Biomembr. 2018 May; 1860(5):973-980.BB

Abstract

Hyperuricemia has been recognized as an independent risk factor for cardiovascular disease. Urate stimulates NADPH oxidase and induces production of reactive oxygen species (ROS); consequently, intracellular urate accumulation can induce oxidative stress leading to endothelial dysfunction. Here, we studied the mechanism involved, using human umbilical vascular endothelial cells (HUVEC) as a model. Pretreatment with 15 mg/dL unlabeled uric acid (corresponding to hyperuricemia) resulted in increased uptake of [14C]uric acid at steady-state by HUVEC, whereas pretreatment with 5 mg/dL uric acid (in the normal serum concentration range) did not. However, the initial uptake rate of [14C]uric acid was not affected by uric acid at either concentration. These results suggest that efflux transport of uric acid is decreased under hyperuricemic conditions. We observed a concomitant decrease of phosphorylated endothelial nitric oxide synthase. Plasma membrane expression of breast cancer resistance protein (BCRP), a uric acid efflux transporter, was decreased under hyperuricemia, though the total cellular expression of BCRP remained constant. Uric acid did not affect expression of another uric acid efflux transporter, multidrug resistance associated protein 4 (MRP4). Moreover, phosphorylation of Akt, which regulates plasma membrane localization of BCRP, was decreased. These uric acid-induced changes of BCRP and Akt were reversed in the presence of the antioxidant N-acetylcysteine. These results suggest that in hyperuricemia, uric acid-induced ROS generation inhibits Akt phosphorylation, causing a decrease in plasma membrane localization of BCRP, and the resulting decrease of BCRP-mediated efflux leads to increased uric acid accumulation and dysregulation of endothelial function.

Authors+Show Affiliations

Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: tamai@p.kanazawa-u.ac.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29317200

Citation

Komori, Hisakazu, et al. "Hyperuricemia Enhances Intracellular Urate Accumulation Via Down-regulation of Cell-surface BCRP/ABCG2 Expression in Vascular Endothelial Cells." Biochimica Et Biophysica Acta. Biomembranes, vol. 1860, no. 5, 2018, pp. 973-980.
Komori H, Yamada K, Tamai I. Hyperuricemia enhances intracellular urate accumulation via down-regulation of cell-surface BCRP/ABCG2 expression in vascular endothelial cells. Biochim Biophys Acta Biomembr. 2018;1860(5):973-980.
Komori, H., Yamada, K., & Tamai, I. (2018). Hyperuricemia enhances intracellular urate accumulation via down-regulation of cell-surface BCRP/ABCG2 expression in vascular endothelial cells. Biochimica Et Biophysica Acta. Biomembranes, 1860(5), 973-980. https://doi.org/10.1016/j.bbamem.2018.01.006
Komori H, Yamada K, Tamai I. Hyperuricemia Enhances Intracellular Urate Accumulation Via Down-regulation of Cell-surface BCRP/ABCG2 Expression in Vascular Endothelial Cells. Biochim Biophys Acta Biomembr. 2018;1860(5):973-980. PubMed PMID: 29317200.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hyperuricemia enhances intracellular urate accumulation via down-regulation of cell-surface BCRP/ABCG2 expression in vascular endothelial cells. AU - Komori,Hisakazu, AU - Yamada,Kazuyuki, AU - Tamai,Ikumi, Y1 - 2018/01/06/ PY - 2017/10/04/received PY - 2017/12/20/revised PY - 2018/01/04/accepted PY - 2018/1/11/pubmed PY - 2018/9/8/medline PY - 2018/1/11/entrez KW - Akt KW - BCRP/ABCG2 KW - Reactive oxygen species KW - Trafficking KW - Uric acid KW - Vascular endothelial cell SP - 973 EP - 980 JF - Biochimica et biophysica acta. Biomembranes JO - Biochim Biophys Acta Biomembr VL - 1860 IS - 5 N2 - Hyperuricemia has been recognized as an independent risk factor for cardiovascular disease. Urate stimulates NADPH oxidase and induces production of reactive oxygen species (ROS); consequently, intracellular urate accumulation can induce oxidative stress leading to endothelial dysfunction. Here, we studied the mechanism involved, using human umbilical vascular endothelial cells (HUVEC) as a model. Pretreatment with 15 mg/dL unlabeled uric acid (corresponding to hyperuricemia) resulted in increased uptake of [14C]uric acid at steady-state by HUVEC, whereas pretreatment with 5 mg/dL uric acid (in the normal serum concentration range) did not. However, the initial uptake rate of [14C]uric acid was not affected by uric acid at either concentration. These results suggest that efflux transport of uric acid is decreased under hyperuricemic conditions. We observed a concomitant decrease of phosphorylated endothelial nitric oxide synthase. Plasma membrane expression of breast cancer resistance protein (BCRP), a uric acid efflux transporter, was decreased under hyperuricemia, though the total cellular expression of BCRP remained constant. Uric acid did not affect expression of another uric acid efflux transporter, multidrug resistance associated protein 4 (MRP4). Moreover, phosphorylation of Akt, which regulates plasma membrane localization of BCRP, was decreased. These uric acid-induced changes of BCRP and Akt were reversed in the presence of the antioxidant N-acetylcysteine. These results suggest that in hyperuricemia, uric acid-induced ROS generation inhibits Akt phosphorylation, causing a decrease in plasma membrane localization of BCRP, and the resulting decrease of BCRP-mediated efflux leads to increased uric acid accumulation and dysregulation of endothelial function. SN - 0005-2736 UR - https://www.unboundmedicine.com/medline/citation/29317200/Hyperuricemia_enhances_intracellular_urate_accumulation_via_down_regulation_of_cell_surface_BCRP/ABCG2_expression_in_vascular_endothelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0005-2736(18)30006-3 DB - PRIME DP - Unbound Medicine ER -