이정표 (서울대학교 의과대학, 서울특별시 보라매병원) | 한빛사논문 > 한빛사

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서울대학교 의과대학, 서울특별시 보라매병원

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Kidney Int., Feb 29 2024, S0085-2538(24)00163-7 | https://doi.org/10.1016/j.kint.2024.01.040 Antibiotic-induced intestinal microbiota depletion can attenuate the acute kidney injury to chronic kidney disease transition via NADPH oxidase 2 and trimethylamine-N-oxide inhibition

Jeonghwan Lee^1,2∗, Jinhaeng Lee ^3∗, Kyuhong Kim ^4∗, Jiwon Lee ⁴, Youngae Jung ³, Jin Seong Hyeon ³, Areum Seo ⁵, Wencheng Jin^1,2, Boram Weon^2,6, Nayeon Shin ², Sejoong Kim ^1,7, Chun Soo Lim^1,2, Yon Su Kim^1,6, Jung Pyo Lee ^1,2†, Geum-Sook Hwang ^3†, Seung Hee Yang ^8,9†

¹Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

²Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea

³Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea

⁴Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

⁵Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea

⁶Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea

⁷Seoul National University Bundang Hospital, Seoul, Republic of Korea

⁸Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea

⁹Kidney Research Institute, Seoul National University, Seoul, Republic of Korea

^∗These two authors contributed equally as co-first authors.

^†These three authors contributed equally as corresponding authors.

Abstract

Intestinal microbiota and their metabolites affect systemic inflammation and kidney disease outcomes. Here, we investigated the key metabolites associated with the acute kidney injury (AKI)-to chronic kidney disease (CKD) transition and the effect of antibiotic-induced microbiota depletion (AIMD) on this transition. In 61 patients with AKI, 59 plasma metabolites were assessed to determine the risk of AKI-to-CKD transition. An AKI-to-CKD transition murine model was established four weeks after unilateral ischemia-reperfusion injury (IRI) to determine the effects of AIMD on the gut microbiome, metabolites, and pathological responses related to CKD transition. Human proximal tubular epithelial cells were challenged with CKD transition-related metabolites and inhibitory effects of NADPH oxidase 2 (NOX2) signals were tested. Based on clinical metabolomics, plasma trimethylamine N-oxide (TMAO) was associated with a significant increased risk for AKI-to-CKD transition [adjusted odds ratio 4.389 (95% confidence interval 1.106-17.416)]. In vivo, AIMD inhibited a unilateral IRI-induced increase in TMAO, along with a decreased in apoptosis, inflammation, and fibrosis. The expression of NOX2 and oxidative stress decreased after AIMD. In vitro, TMAO induced fibrosis with NOX2 activation and oxidative stress. NOX2 inhibition successfully attenuated apoptosis, inflammation, and fibrosis with suppression of G2/M arrest. NOX2 inhibition (in vivo) showed improvement in pathological changes with a decrease in oxidative stress without changes in TMAO levels. Thus, TMAO is a key metabolite associated with the AKI-to-CKD transition and NOX2 activation was identified as a key regulator of TMAO-related AKI-to-CKD transition both in vivo and in vitro.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-03-04)
연구진국내 연구진
분야 의약학 > 의약학 기타

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