연구성과 홍보

Exp Mol Med. 2024 Feb;56(2):355-369.

Title : Targeting the m6A RNA methyltransferase METTL3 attenuates the development of kidney fibrosis

Authors : Hae Rim Jung#1, Jeonghwan Lee#2,3, Seung-Pyo Hong1,4, Nayeon Shin3, Ara Cho2, Dong-Jin Shin5, Jin Woo Choi6, Jong-Il Kim1,4,7, Jung Pyo Lee8,9*, Sung-Yup Cho10,11,12*

Affiliations :

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.

8Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

9Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.

10Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.

11Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.

12Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.

DOI: doi: 10.1038/s12276-024-01159-5.

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.