Depletion of Uric Acid Due to SLC22A12 (URAT1) Loss-of-Function Mutation Causes Endothelial Dysfunction in Hypouricemia

Shinobu Sugihara; Ichiro Hisatome; Masanari Kuwabara; Koichiro Niwa; Nani Maharani; Masahiko Kato; Kazuhide Ogino; Toshihiro Hamada; Haruaki Ninomiya; Yukihito Higashi; Kimiyoshi Ichida; Kazuhiro Yamamoto

doi:10.1253/circj.CJ-14-1267

Vascular Biology and Vascular Medicine

Depletion of Uric Acid Due to SLC22A12 (URAT1) Loss-of-Function Mutation Causes Endothelial Dysfunction in Hypouricemia

Shinobu Sugihara, Ichiro Hisatome, Masanari Kuwabara, Koichiro Niwa, Nani Maharani, Masahiko Kato, Kazuhide Ogino, Toshihiro Hamada, Haruaki Ninomiya, Yukihito Higashi, Kimiyoshi Ichida, Kazuhiro Yamamoto

Author information

Shinobu Sugihara
Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics Faculty of Medicine, Tottori University
Ichiro Hisatome
Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science
Masanari Kuwabara
Department of Cardiology, St. Luke’s International Hospital
Koichiro Niwa
Department of Cardiology, St. Luke’s International Hospital
Nani Maharani
Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science
Masahiko Kato
Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics Faculty of Medicine, Tottori University
Kazuhide Ogino
Department of Clinical Laboratory, Tottori University Hospital
Toshihiro Hamada
Department of Regional Medicine, Tottori University Faculty of Medicine
Haruaki Ninomiya
Department of Biological Regulation, Tottori University Faculty of Medicine
Yukihito Higashi
Department of Regeneration and Medicine, Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine Hiroshima University
Kimiyoshi Ichida
Department of Pathophysiology, Tokyo University of Pharmacy and Life science
Kazuhiro Yamamoto
Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics Faculty of Medicine, Tottori University

Keywords: Hypouricemia, Uric acid, Uric acid transporter 1, Vascular function

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Supplementary material

2015 Volume 79 Issue 5 Pages 1125-1132

DOI https://doi.org/10.1253/circj.CJ-14-1267

Editorial (79-5 pp. 978-980)

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Abstract

Background:Uric acid (UA) serves as an antioxidant in vascular endothelial cells. UA transporter 1 (URAT1) encoded by SLC22A12 is expressed in the kidney and vessels and its loss of function causes hypouricemia. The purpose of this study was to examine whether there is any endothelial dysfunction in patients with hypouricemia.Methods and Results:Twenty-six patients with hypouricemia (<2.5 mg/dl) and 13 healthy control subjects were enrolled. Endothelial function was evaluated using flow-mediated dilation (FMD). mRNA of UA transporters expressed in cultured human umbilical endothelial cells (HUVEC) was detected on RT-PCR. There was a positive correlation between FMD and serum UA in the hypouricemia group. URAT1 loss-of-function mutations were found in the genome of 21 of 26 patients with hypouricemia, and not in the other 5. In the hypouricemia groups, serum UA in homozygous and compound heterozygous patients was significantly lower than in other groups, suggesting that severity of URAT1 dysfunction may influence the severity of hypouricemia. Thirteen of 16 hypouricemia subjects with homozygous and compound heterozygote mutations had SUA <0.8 mg/dl and their FMD was lower than in other groups. HUVEC do not express mRNA of URAT1, suggesting the null role of URAT1 in endothelial function.Conclusions:Depletion of UA due to SLC22A12/URAT1 loss-of-function mutations causes endothelial dysfunction in hypouricemia patients. (Circ J 2015; 79: 1125–1132)

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