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

被引：12

作者：

Jung, Hae Rim ^{[1
]}

Lee, Jeonghwan ^{[2
,3
]}

Hong, Seung-Pyo ^{[1
,4
]}

Shin, Nayeon ^{[3
]}

Cho, Ara ^{[2
]}

Shin, Dong-Jin ^{[5
]}

Choi, Jin Woo ^{[6
]}

Kim, Jong-Il ^{[1
,4
,7
]}

Lee, Jung Pyo ^{[2
,3
]}

Cho, Sung-Yup ^{[1
,4
,7
]}

机构：

[1] Seoul Natl Univ, Genom Med Inst, Med Res Ctr, Seoul, South Korea

[2] Seoul Natl Univ, Dept Internal Med, Coll Med, Seoul, South Korea

[3] Seoul Natl Univ, Dept Internal Med, Boramae Med Ctr, Seoul, South Korea

[4] Seoul Natl Univ, Dept Biomed Sci, Coll Med, Seoul, South Korea

[5] Seoul Natl Univ, Med Major, Coll Med, Seoul, South Korea

[6] Kyung Hee Univ, Coll Pharm, Seoul, South Korea

[7] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea

来源：

EXPERIMENTAL AND MOLECULAR MEDICINE | 2024年 / 56卷 / 02期

基金：

新加坡国家研究基金会;

关键词：

NET1;

D O I：

10.1038/s12276-024-01159-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Kidney fibrosis is a major mechanism underlying chronic kidney disease (CKD). N-6-methyladenosine (m(6)A) RNA methylation is associated with organ fibrosis. We investigated m(6)A profile alterations and the inhibitory effect of RNA methylation in kidney fibrosis in vitro (TGF-beta-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 m(6)A levels. In the UUO model, METTL3 expression and m6A levels were significantly increased. Transcriptomic and m(6)A profiling demonstrated that epithelial-to-mesenchymal transition- and inflammation-related pathways were significantly associated with RNA m(6)A methylation. Genetic and pharmacologic inhibition of METTL3 in HK-2 cells decreased TGF-beta-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.

引用

页码：355 / 369

页数：15