Long noncoding RNA NEAT1 is involved in the protective effect of Klotho on renal tubular epithelial cells in diabetic kidney disease through the ERK1/2 signaling pathway

Yan-Lin Yang; Meng Xue; Yijie Jia; Fang Hu; Zongji Zheng; Ling Wang; Ze-Kun Si; Yaoming Xue

doi:10.1038/s12276-020-0381-5

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자료유형: 학술저널

저자정보: Yan-Lin Yang (Southern Medical University) Meng Xue (Southern Medical University) Yijie Jia (Southern Medical University) Fang Hu (Southern Medical University) Zongji Zheng (Southern Medical University) Ling Wang (Southern Medical University) Ze-Kun Si (Southern Medical University) Yaoming Xue (Southern Medical University)

저널정보: 대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine 제52권

발행연도: 2020.2

수록면: 1 - 15 (15page)

DOI: 10.1038/s12276-020-0381-5

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Klotho, an antiaging protein, has been shown to play a protective role in renal tubular epithelial-mesenchymal transition (EMT) during the development of diabetic kidney disease (DKD). Long noncoding RNAs (lncRNAs) participate in the progression of EMT in many diseases. However, the effect of Klotho on lncRNAs during the development of DKD is still unknown. In this study, we found that Klotho overexpression in high-fat diet (HFD)- and streptozotocin (STZ)- induced DKD mice significantly inhibited the expression of lncRNA nuclear-enriched abundant transcript 1 (Neat1). We demonstrated that NEAT1 was significantly upregulated in both bovine serum albumin (BSA)-stimulated HK2 cells and mice with HFD- and STZ-induced diabetes. In addition, we observed that Klotho displays colocalization with NEAT1. Furthermore, overexpression of Klotho can inhibit the high expression of NEAT1 in BSA-stimulated HK2 cells, while silencing Klotho can further upregulate the expression of NEAT1. Silencing NEAT1 in HK2 cells resulted in inhibition of the EMT-related markers alpha smooth muscle actin (α-SMA) and vimentin (VIM) and the renal fibrosis-related markers transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). The effect of NEAT1 on DKD was partly mediated by regulation of the ERK1/2 signaling pathway. Finally, we found that silencing NEAT1 can reverse the activation of EMT and fibrosis caused by Klotho silencing in a manner dependent on the ERK1/2 signaling pathway. These findings reveal a new regulatory pathway by which Klotho regulates ERK1/2 signaling via NEAT1 to protect against EMT and renal fibrosis, suggesting that NEAT1 is a potential therapeutic target for DKD.

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