m6A-induced lncRNA MALAT1 aggravates renal fibrogenesis in obstructive nephropathy through the miR-145/FAK pathway

Aging (Albany NY). 2020 Mar 23;12(6):5280-5299. doi: 10.18632/aging.102950. Epub 2020 Mar 23.

Abstract

Renal fibrosis is a key factor in chronic kidney disease (CKD). Long non-coding RNAs (lncRNAs) play important roles in the physiological and pathological progression of human diseases. However, the roles and underlying mechanisms of lncRNAs in renal fibrosis still need to be discovered. In this study, we first displayed the increased lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression in renal fibrosis in patients with obstructive nephropathy (ON). Then we found that transforming growth factor beta 1 (TGF-β1) induced epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) protein deposition, which promoted the viability, proliferation and migration of human renal proximal tubular epithelial (HK2) cells. Next, MALAT1/miR-145/focal adhesion kinase (FAK) pathway was confirmed to play an importment role in TGF-β1-induced renal fibrosis. In addition, the MALAT1/miR-145/FAK pathway was involved in the effect of dihydroartemisinin (DHA) on TGF-β1-induced renal fibrosis in vitro and in vivo. Furthermore, m6A methyltransferase methyltransferase-like 3 (METTL3) was shown to be the main methyltransferase of m6A modification on MALAT1.

Keywords: MALAT1; TGF-β1; dihydroartemisinin; mA 6; renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / genetics
  • Animals
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics
  • Fibrosis
  • Focal Adhesion Protein-Tyrosine Kinases / genetics*
  • Humans
  • Kidney / pathology
  • Kidney Diseases / genetics*
  • Kidney Diseases / pathology
  • Male
  • Methyltransferases / genetics
  • Mice
  • MicroRNAs / genetics*
  • RNA, Long Noncoding / genetics*
  • Signal Transduction
  • Transforming Growth Factor beta1 / genetics

Substances

  • MALAT1 long non-coding RNA, human
  • MIRN145 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • N-methyladenosine
  • Methyltransferases
  • METTL3 protein, human
  • Focal Adhesion Protein-Tyrosine Kinases
  • Adenosine