Kidney international · 2025
The m7G methyltransferase METTL1 promotes acute kidney inflammation by disrupting mitochondrial function.
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Xie Shuai-Shuai, Dong Yu-Hang, Gao Jian, Li Wei, Xu Long, Wang Jia-Nan, Yu Ju-Tao, Hou Chao, Li Chao, Gao Ying-Ying, Dong Ze-Hui, Ma Wen-Xian, Hou Rui, Sun Shuai, Ji Ming-Lu, He Ruo-Bing, Suo Xiao-Guo, Ni Wei-Jian, Wen Jia-Gen, Jin Juan, Yang Qin, Cai Hong, Meng Xiao-Ming
Аннотация
INTRODUCTION: RNA modifications regulate the progression of inflammatory diseases. However, the role of N7-methylguanosine (m7G) modification and its regulatory enzyme, methyltransferase-like 1 (METTL1), in inflammatory kidney diseases remains poorly understood. Here, we aimed to investigate the function and underlying mechanisms of METTL1-mediated m7G modification in acute kidney injury (AKI).
METHODS: Kidney tubular epithelial cell (TEC)-specific METTL1 conditional knockout mice were used to evaluate the functional role of METTL1 in multiple AKI mouse models (cisplatin, ischemia/reperfusion and cecal ligation/puncture). Additionally, kidney tissue was obtained from patients with AKI and from the non-tumor kidney tissue of patients with nephrectomy for kidney cancer. RNA sequencing and m7G-methylated RNA immunoprecipitation sequencing were performed to identify downstream targets and elucidate underlying mechanisms.
RESULTS: Both m7G modification and METTL1 expression were markedly upregulated in TECs from patients and mice with AKI. TEC-specific deletion of METTL1 significantly attenuated kidney injury and inflammation in the multiple AKI mouse models. Mechanistically, METTL1-mediated m7G modification enhanced the stability of the TEA domain transcription factor 2 (TEAD2) mRNA by the binding protein Quaking. Elevated TEAD2 impaired mitochondrial function by transcriptionally repressing medium-chain acyl-CoA dehydrogenase (ACADM), thereby amplifying proinflammatory responses. METTL1 knockdown mediated by tetrahedral framework DNA nanostructures, as well as pharmacological inhibition with AZD1080, a novel METTL1 inhibitor, effectively alleviated the severity of AKI in mice in prevention and therapeutic approaches.
CONCLUSIONS: Our findings suggest that targeting the METTL1/TEAD2/ACADM axis may represent a potential therapeutic strategy for inflammatory kidney diseases.
METHODS: Kidney tubular epithelial cell (TEC)-specific METTL1 conditional knockout mice were used to evaluate the functional role of METTL1 in multiple AKI mouse models (cisplatin, ischemia/reperfusion and cecal ligation/puncture). Additionally, kidney tissue was obtained from patients with AKI and from the non-tumor kidney tissue of patients with nephrectomy for kidney cancer. RNA sequencing and m7G-methylated RNA immunoprecipitation sequencing were performed to identify downstream targets and elucidate underlying mechanisms.
RESULTS: Both m7G modification and METTL1 expression were markedly upregulated in TECs from patients and mice with AKI. TEC-specific deletion of METTL1 significantly attenuated kidney injury and inflammation in the multiple AKI mouse models. Mechanistically, METTL1-mediated m7G modification enhanced the stability of the TEA domain transcription factor 2 (TEAD2) mRNA by the binding protein Quaking. Elevated TEAD2 impaired mitochondrial function by transcriptionally repressing medium-chain acyl-CoA dehydrogenase (ACADM), thereby amplifying proinflammatory responses. METTL1 knockdown mediated by tetrahedral framework DNA nanostructures, as well as pharmacological inhibition with AZD1080, a novel METTL1 inhibitor, effectively alleviated the severity of AKI in mice in prevention and therapeutic approaches.
CONCLUSIONS: Our findings suggest that targeting the METTL1/TEAD2/ACADM axis may represent a potential therapeutic strategy for inflammatory kidney diseases.