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A Possible Therapeutic Application of The Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease: A Significance of Inhibition of Urate Transporter 1 and Non-inhibition of Other Urate Transporters for Such Diseases
Yanai, H.; Adachi, H.; Hakoshima, M.; Iida, S.; Katsuyama, H. A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease. Cells2024, 13, 450.
Yanai, H.; Adachi, H.; Hakoshima, M.; Iida, S.; Katsuyama, H. A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease. Cells 2024, 13, 450.
Yanai, H.; Adachi, H.; Hakoshima, M.; Iida, S.; Katsuyama, H. A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease. Cells2024, 13, 450.
Yanai, H.; Adachi, H.; Hakoshima, M.; Iida, S.; Katsuyama, H. A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease. Cells 2024, 13, 450.
Abstract
Renal uric acid (UA) reabsorption is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9). Dotinurad selectively inhibits URAT1 and do not inhibit other UA transporters such as GLUT9, ATP-binding cassette transporter G2 (ABCG2) and organic anion transporter1/3 (OAT1/3). We discovered that dotinurad improved metabolic parameters and renal function in hyperuricemic patients. We consider a significance of high selectivity in inhibiting URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). Dotinurad inhibits selectively URAT1 and increases UA in the proximal tubules, and UA may compete with glucose for GLUT9, reducing glucose reabsorption. The inhibition of UA entry via URAT1 to liver and adipose tissues by dotinurad increased energy expenditure and decrease lipid synthesis and inflammation in rats. The inhibition of URAT1 in kidney, liver and adipose tissues improve metabolic parameters. CKD patients accumulate uremic toxins such as indoxyl sulfate (IS) in the body. ABCG2 regulates renal and intestinal excretion of IS which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into kidney, increasing plasma IS, which produces oxidative stress, inducing vascular endothelial dysfunction in CKD patients. The high-selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD and CVD.
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