2. Academic Validation
  3. METTL14 downregulates GLUT9 through m6A methylation and attenuates hyperuricemia-induced fibrosis in mouse renal tubular epithelial cells

METTL14 downregulates GLUT9 through m6A methylation and attenuates hyperuricemia-induced fibrosis in mouse renal tubular epithelial cells

  • Int Immunopharmacol. 2024 Dec 25;143(Pt 1):113308. doi: 10.1016/j.intimp.2024.113308.
Jianan Yang 1,  Tonglian Jiang 2,  Xun Lu 2,  Xiang Li 3,  Xuling Zhou 2,  Xinxin Guo 2,  Chengxin Ma 2,  Xiaobei Xie 2,  Dongxiao Li 2,  Siqi Yu 2,  Jiayi An 2,  Binghai Zhao 4,  Hongzhi Li 5
Affiliations

Affiliations

  • 1 Nephrosis Precision Medicine Innovation Center, Beihua University School of Basic Medical Science, Jilin 132011, Jilin, China; Department of Clinical Laboratory, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing 100029, China.
  • 2 Nephrosis Precision Medicine Innovation Center, Beihua University School of Basic Medical Science, Jilin 132011, Jilin, China.
  • 3 Nephrosis Precision Medicine Innovation Center, Beihua University School of Basic Medical Science, Jilin 132011, Jilin, China; Jilin Province Science and Technology Innovation Center of Kidney Disease Precision Medicine Based on Gene Sequencing, Beihua University, Jilin 132011, Jilin, China.
  • 4 Nephrosis Precision Medicine Innovation Center, Beihua University School of Basic Medical Science, Jilin 132011, Jilin, China; Jilin Province Science and Technology Innovation Center of Kidney Disease Precision Medicine Based on Gene Sequencing, Beihua University, Jilin 132011, Jilin, China. Electronic address: zhaobinghai01@vip.163.com.
  • 5 Nephrosis Precision Medicine Innovation Center, Beihua University School of Basic Medical Science, Jilin 132011, Jilin, China; Jilin Province Science and Technology Innovation Center of Kidney Disease Precision Medicine Based on Gene Sequencing, Beihua University, Jilin 132011, Jilin, China. Electronic address: hongzhi-li2008@163.com.
PMID: 39393275 DOI: 10.1016/j.intimp.2024.113308
Abstract

Hyperuricemia is a known risk factor for chronic kidney disease (CKD) and subsequent renal fibrosis. N6-methyladenosine (m6A) is the most prevalent chemical modification in eukaryotic mRNAs and has been implicated in various diseases. However, its role in hyperuricemic nephropathy (HN) remains unclear. This study investigated the involvement of the methylase METTL14 in HN pathogenesis. Our in vitro and in vivo function experiments demonstrated that METTL14 plays a crucial role in HN. In mouse models of uric acid (UA)-induced renal injury, we detected impaired kidney function, increased renal interstitial fibrosis, and significantly decreased m6A methylation levels in renal tissues. Treatment with benzbromarone, a UA-lowering drug, alleviated renal injury, restored m6A methylation levels, and upregulated METTL14 expression. Cellular experiments showed that METTL14 overexpression attenuated high UA-induced fibrosis in renal tubular epithelial cells. This overexpression significantly decreases the expression of GLUT9, a key protein involved in UA transport, leading to reduced UA reabsorption. Additionally, MeRIP-qPCR and dual-luciferase reporter gene experiments further demonstrated that METTL14 overexpression enhanced Glut9 mRNA m6A methylation modification, accelerating its degradation and decreasing expression levels. Thus, METTL14-mediated RNA m6A modification plays a role in the renal tubular epithelial cell damage induced by high UA, by regulating Glut9 mRNA post-transcriptionally. These findings provide valuable insights for the diagnosis and development of therapeutic drugs for HN.

Keywords

GLUT9; Hyperuricemic nephropathy; METTL14; Renal fibrosis; Urate reabsorption; m6A.

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