A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease

Abstract

The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD.

Keywords: ATP-binding cassette transporter G2; chronic kidney disease; dotinurad; hyperuricemia; organic anion transporter1/3; urate transporter 1.

Figure 1

Urate transporters in the kidneys and intestine. Black arrows indicate the flow of uric acid and uremic toxins. ABCG2—ATP-binding cassette transporter G2; GLUT9—glucose transporter 9; OAT—organic anion transporter; UA—uric acid; URAT1—urate transporter 1; UT—uremic toxin.

Figure 2

Changes in UA transport by UA transporters in the kidneys and intestine by insulin resistance and hyperinsulinemia. Upward- and downward-facing arrows indicate increase or decrease in substances or expression of molecules, respectively. Right arrow and ? indicate no change and no available data about change of substances or expression of molecules, respectively. ABCG2—ATP-binding cassette transporter G2; GLUT9—glucose transporter 9; OAT—organic anion transporter; UA—uric acid; URAT1—urate transporter 1.

Figure 3

The possible mechanisms of an improvement in metabolic parameters by dotinurad. Upward- and downward-facing arrows indicate increase or decrease in substances or expression of molecules, respectively. ABCG2—ATP-binding cassette transporter G2; CPT-1—carnitine palmitoyl-transferase 1; FA—fatty acid; GLUT9—glucose transporter 9; PPARα—proliferator-activated receptor alpha; ROS—reactive oxygen species; SCD-1—stearoyl-CoA desaturase 1; SREBP-1c—sterol regulatory element-binding protein 1c; TNF-α—tumor necrosis factor-alpha; UA—uric acid; UCP1—uncoupling protein 1; URAT1—urate transporter 1; VLDL—very-low-density lipoprotein.

Figure 4

Changes in UA transport by urate transporters in the kidneys and intestine by CKD progression. Upward- and downward-facing arrows indicate increase or decrease in substances or expression of molecules, respectively. ? indicates no available data about change of substances or expression of molecules. ABCG2—ATP-binding cassette transporter G2; CKD—chronic kidney disease; CVD—cardiovascular disease; GLUT9—glucose transporter 9; OAT—organic anion transporter; UA—uric acid; URAT1—urate transporter 1.

Figure 5

A summary of unfavorable effects of the inhibition of ABCG2, OAT1, and OAT3 on the kidneys and vascular endothelial cells in CKD patients. Upward- and downward-facing arrows indicate increase or decrease in substances. ABCG2—ATP-binding cassette transporter G2; GLUT9—glucose transporter 9; IL-1β—interleukin-1b; OAT—organic anion transporter; ROS—reactive oxygen species; UA—uric acid; UT—uremic toxin.

Figure 6

A summary of beneficial effects of dotinurad on the kidneys and atherosclerosis in CKD patients. Upward- and downward-facing black arrows indicate increase or decrease in substances. ABCG2—ATP-binding cassette transporter G2; EC—endothelial cells; OAT—organic anion transporter; ROS—reactive oxygen species; SMC—smooth muscle cells; UA—uric acid; URAT1—urate transporter 1; UT—uremic toxin.

Figure 7

The pathophysiology of metabolic syndrome and effects of dotinurad. Red lines indicate effects of dotinurad. CKD—chronic kidney disease; CVD—cardiovascular disease.