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

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이정환Jeonghwan Lee

서울대학교 의과대학, 서울특별시 보라매병원

Exp. Mol. Med., 01 February 2024 | https://doi.org/10.1038/s12276-024-01159-5 Targeting the m6A RNA methyltransferase METTL3 attenuates the development of kidney fibrosis

Hae Rim Jung ^1,8, Jeonghwan Lee^2,3,8, Seung-Pyo Hong^1,4, Nayeon Shin ³, Ara Cho ², Dong-Jin Shin ⁵, Jin Woo Choi ⁶, Jong-Il Kim ^1,4,7, Jung Pyo Lee^2,3,* and Sung-Yup Cho ^1,4,7,*

¹Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.²Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
³Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
⁴Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁵Medicine Major, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁶College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
⁷Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
⁸These authors contributed equally: Hae Rim Jung, Jeonghwan Lee.

^*Corresponding authors: correspondence to Jung Pyo Lee or Sung-Yup Cho

Abstract

Kidney fibrosis is a major mechanism underlying chronic kidney disease (CKD). N⁶-methyladenosine (m⁶A) RNA methylation is associated with organ fibrosis. We investigated m⁶A profile alterations and the inhibitory effect of RNA methylation in kidney fibrosis in vitro (TGF-β-treated HK-2 cells) and in vivo (unilateral ureteral obstruction [UUO] mouse model). METTL3-mediated signaling was inhibited using siRNA in vitro or the METTL3-specific inhibitor STM2457 in vivo and in vitro. In HK-2 cells, METTL3 protein levels increased in a dose- and time-dependent manner along with an increase in the cellular m⁶A levels. In the UUO model, METTL3 expression and m⁶A levels were significantly increased. Transcriptomic and m⁶A profiling demonstrated that epithelial-to-mesenchymal transition- and inflammation-related pathways were significantly associated with RNA m6A methylation. Genetic and pharmacologic inhibition of METTL3 in HK-2 cells decreased TGF-β-induced fibrotic marker expression. STM2457-induced inhibition of METTL3 attenuated the degree of kidney fibrosis in vivo. Furthermore, METTL3 protein expression was significantly increased in the tissues of CKD patients with diabetic or IgA nephropathy. Therefore, targeting alterations in RNA methylation could be a potential therapeutic strategy for treating kidney fibrosis.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-01)
연구진국내 연구진
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