URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease

Yoshiro Tanaka; Tomohisa Nagoshi; Hirotake Takahashi; Yuhei Oi; Rei Yasutake; Akira Yoshii; Haruka Kimura; Yusuke Kashiwagi; Toshikazu D Tanaka; Masayuki Shimoda; Michihiro Yoshimura

doi:10.1016/j.isci.2023.107730

URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease

iScience. 2023 Aug 25;26(9):107730. doi: 10.1016/j.isci.2023.107730. eCollection 2023 Sep 15.

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.
² Department of Pathology, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.

Abstract

We recently reported that the selective inhibition of urate transporter-1 (URAT1), which is primarily expressed in the kidneys, ameliorates insulin resistance by attenuating hepatic steatosis and improving brown adipose tissue function in diet-induced obesity. In this study, we evaluated the effects of dotinurad, a URAT1-selective inhibitor, on the hearts of high-fat diet (HFD)-fed obese mice for 16-20 weeks and on neonatal rat cardiomyocytes (NRCMs) exposed to palmitic acid. Outside the kidneys, URAT1 was also expressed in cardiomyocytes and indeed worked as a uric acid transporter. Dotinurad substantially attenuated HFD-induced cardiac fibrosis, inflammatory responses, and cardiac dysfunction. Intriguingly, among various factors related to the pathophysiology of diet-induced obesity, palmitic acid significantly increased URAT1 expression in NRCMs and subsequently induced apoptosis, oxidative stress, and inflammatory responses via MAPK pathway, all of which were reduced by dotinurad. These results indicate that URAT1 is a potential therapeutic target for metabolic heart disease.

Keywords: Cell biology; Pathophysiology; Physiology.