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.
Highlights
With the rising prevalence of diabetes mellitus in recent decades, diabetic kidney disease (DKD) has become more common than glomerulonephritis nephropathy in China[1]
We found that silencing NEAT1 eliminated the increases in transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), vimentin, and α-SMA caused by transfection with si-Klotho in HK-2 cells (Fig. 8b–e), as well as the increases in cell migration (Supplemental Fig. 2a, b)
The phosphorylation of ERK1/2 was inhibited by transfection with si-NEAT1 (Fig. 8f). These results indicate that NEAT1 is involved in the protective effect of Klotho against fibrosis and epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells, partly through the ERK1/2 signaling pathway
Summary
With the rising prevalence of diabetes mellitus in recent decades, diabetic kidney disease (DKD) has become more common than glomerulonephritis nephropathy in China[1]. 40–45% of patients with type 1 diabetes mellitus (T1DM) develop DKD and progress to end-stage renal disease (ESRD) or die before its onset[2]. Increasing evidence suggests that renal tubules play a causative role in Albumin is a key factor for promoting EMT in renal tubular epithelial cells in DKD6,7. It is of great significance to explore the pathophysiological mechanism in the renal tubules during the progression of DKD. Studies have confirmed that decreased Klotho levels in the early stage of T2DM can predict renal function decline[9]. Klotho deficiency exacerbates early tubulointerstitial fibrosis in DKD mice, and recombinant Klotho therapy can significantly improve renal function and renal fibrosis[10,11,12]. The precise molecular mechanisms by which Klotho regulates EMT and tubulointerstitial fibrosis during the progression of DKD are largely unknown
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