URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease
Summary: 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 th...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223018072 |
| _version_ | 1797693926090473472 |
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| author | Yoshiro Tanaka Tomohisa Nagoshi Hirotake Takahashi Yuhei Oi Rei Yasutake Akira Yoshii Haruka Kimura Yusuke Kashiwagi Toshikazu D. Tanaka Masayuki Shimoda Michihiro Yoshimura |
| author_facet | Yoshiro Tanaka Tomohisa Nagoshi Hirotake Takahashi Yuhei Oi Rei Yasutake Akira Yoshii Haruka Kimura Yusuke Kashiwagi Toshikazu D. Tanaka Masayuki Shimoda Michihiro Yoshimura |
| author_sort | Yoshiro Tanaka |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-12T02:50:42Z |
| format | Article |
| id | doaj.art-d3ca071ededb4a32b53ae9e2375ad775 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-12T02:50:42Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-d3ca071ededb4a32b53ae9e2375ad7752023-09-04T04:10:35ZengElsevieriScience2589-00422023-09-01269107730URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart diseaseYoshiro Tanaka0Tomohisa Nagoshi1Hirotake Takahashi2Yuhei Oi3Rei Yasutake4Akira Yoshii5Haruka Kimura6Yusuke Kashiwagi7Toshikazu D. Tanaka8Masayuki Shimoda9Michihiro Yoshimura10Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; Corresponding authorDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Pathology, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004223018072Cell biologyPathophysiologyPhysiology |
| spellingShingle | Yoshiro Tanaka Tomohisa Nagoshi Hirotake Takahashi Yuhei Oi Rei Yasutake Akira Yoshii Haruka Kimura Yusuke Kashiwagi Toshikazu D. Tanaka Masayuki Shimoda Michihiro Yoshimura URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease iScience Cell biology Pathophysiology Physiology |
| title | URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease |
| title_full | URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease |
| title_fullStr | URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease |
| title_full_unstemmed | URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease |
| title_short | URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease |
| title_sort | urat1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet induced metabolic heart disease |
| topic | Cell biology Pathophysiology Physiology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223018072 |
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