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.

中文翻译：

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长非编码RNA NEAT1通过ERK1 / 2信号通路参与Klotho对糖尿病肾病肾小管上皮细胞的保护作用。

Klotho是一种抗衰老蛋白，在糖尿病性肾脏病（DKD）的发展过程中，已被证明在肾小管上皮-间质转化（EMT）中起保护作用。长的非编码RNA（lncRNA）参与许多疾病的EMT进展。然而，在DKD的发展过程中，Klotho对lncRNA的作用仍然未知。在这项研究中，我们发现高脂饮食（HFD）和链脲佐菌素（STZ）诱导的DKD小鼠中Klotho过表达显着抑制了lncRNA富核转录本1（Neat1）的表达。我们证明，NEAT1在牛血清白蛋白（BSA）刺激的HK2细胞和HFD和STZ诱导的糖尿病小鼠中均显着上调。此外，我们观察到Klotho与NEAT1显示共定位。此外，Klotho的过度表达可以抑制BSA刺激的HK2细胞中NEAT1的高表达，而沉默Klotho可以进一步上调NEAT1的表达。沉默HK2细胞中的NEAT1可抑制EMT相关标志物α平滑肌肌动蛋白（α-SMA）和波形蛋白（VIM）以及肾纤维化相关标志物转化生长因子-β1（TGF-β1）和结缔组织生长因子（CTGF）。NEAT1对DKD的影响部分由ERK1 / 2信号通路的调节介导。最后，我们发现沉默NEAT1可以以依赖ERK1 / 2信号传导途径的方式逆转由Klotho沉默引起的EMT和纤维化的激活。这些发现揭示了Klotho通过NEAT1调节ERK1 / 2信号传导以防止EMT和肾纤维化的新调节途径，