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

Abstract

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.

Kidney disease: Effect of an anti-aging protein

An anti-ageing protein called Klotho helps protect against kidney failure in mice and human cells by silencing a long non-coding RNA molecule. The regulatory RNA involved, known as NEAT1, promotes cellular transformations associated with the disease process. A team led by Yao-Ming Xue from Southern Medical University in Guangdong, China, showed that levels of NEAT1 are elevated in mouse models of diabetic kidney disease and in injured human kidney calls. The identification of NEAT1 in kidney disease thus provides a novel therapeutic target. After demonstrating that Klotho and NEAT1 interact directly with each other in cells, they experimentally boosted Klotho expression and observed suppressed levels of NEAT1. As a consequence, the cells displayed lower levels of the proteins linked to the progressive deposition of fibrosis in the kidneys.