이인규 (경북대학교 의과대학)

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경북대학교 의과대학

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Kidney Int., 2023 Jul 1;S0085-2538(23)00477-5 | https://doi.org/10.1016/j.kint.2023.06.022 Inhibition of pyruvate dehydrogenase kinase 4 ameliorates kidney ischemia-reperfusion injury by reducing succinate accumulation during ischemia and preserving mitochondrial function during reperfusion

Chang Joo Oh^1,17, Min-Ji Kim^2,17, Ji-Min Lee ^3,17, Dong Hun Kim ⁴, Il-Young Kim ^5,6, Sanghee Park ⁷, Yeongmin Kim ⁸, Kyung-Bok Lee ⁹, Sang-Hee Lee ⁹, Chae Won Lim ¹⁰, Myeongjin Kim ¹⁰, Jung-Yi Lee ¹, Haushabhau S Pagire ¹¹, Suvarna H Pagire ¹¹, Myung Ae Bae ¹², Dipanjan Chanda ¹, Themis Thoudam ¹, Ah Reum Khang ¹³, Robert A Harris ¹⁴, Jin Hee Ahn ^15,18, Jae-Han Jeon ^16,18, In-Kyu Lee ^16,18

¹Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea
²Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
³Cell & Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea
⁴Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea
⁵Department of Molecular Medicine, College of Medicine, Gachon University, Incheon, Republic of Korea
⁶Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
⁷Department of Exercise Rehabilitation, Gachon University, Incheon, Republic of Korea
⁸Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea
⁹Center for Research Equipment (104-Dong), Korea Basic Science Institute, Ochang, Cheongju, Chungbuk, Republic of Korea
¹⁰Department of Medicine, Graduate School, Daegu Catholic University, Gyeongsan, Gyeongbuk, Republic of Korea
¹¹Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
¹²Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
¹³Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University College of Medicine, Yangsan, Republic of Korea
¹⁴Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
¹⁵Department of Chemistry, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea.
¹⁶Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hoguk-ro, Buk-gu, Daegu 41404, Republic of Korea.
¹⁷CJO, M-JK, and J-ML contributed equally to this work as first authors.
¹⁸JHA, J-HJ, and I-KL contributed equally to this work as corresponding authors.

Correspondence: Jin Hee Ahn, Jae-Han Jeon, In-Kyu Lee

Abstract

Ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury (AKI), is still without effective therapies. Succinate accumulation during ischemia followed by its oxidation during reperfusion leads to excessive reactive oxygen species (ROS) and severe kidney damage. Consequently, the targeting of succinate accumulation may represent a rational approach to the prevention of IR-induced kidney injury. Since ROS are generated primarily in mitochondria, which are abundant in the proximal tubule of the kidney, we explored the role of pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial enzyme, in IR-induced kidney injury using proximal tubule cell-specific Pdk4 knockout (Pdk4^ptKO) mice. Knockout or pharmacological inhibition of PDK4 ameliorated IR-induced kidney damage. Succinate accumulation during ischemia, which is responsible for mitochondrial ROS production during reperfusion, was reduced by PDK4 inhibition. PDK4 deficiency established conditions prior to ischemia resulting in less succinate accumulation, possibly because of a reduction in electron flow reversal in complex II, which provides electrons for the reduction of fumarate to succinate by succinate dehydrogenase during ischemia. The administration of dimethyl succinate, a cell-permeable form of succinate, attenuated the beneficial effects of PDK4 deficiency, suggesting that the kidney-protective effect is succinate-dependent. Finally, genetic or pharmacological inhibition of PDK4 prevented IR-induced mitochondrial damage in mice and normalized mitochondrial function in an in vitro model of IR injury. Thus, inhibition of PDK4 represents a novel means of preventing IR-induced kidney injury, and involves the inhibition of ROS-induced kidney toxicity through reduction in succinate accumulation and mitochondrial dysfunction.

논문정보

형식Research article
게재일2023년 07월 (BRIC 등록일 2023-07-26)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

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