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Yijie Jia,Zongji Zheng,Meiping Guan,Qian Zhang,Yang Li,Ling Wang,Yaoming Xue 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-
Extracellular vesicles (EVs), which contain microRNA (miRNA), constitute a novel means of cell communication that may contribute to the inevitable expansion of renal fibrosis during diabetic kidney disease (DKD). Exendin-4 is effective for treating DKD through its action on GLP1R. However, the effect of exendin-4 on EV miRNA expression and renal cell communication during the development of DKD remains unknown. In this study, we found that EVs derived from HK-2 cells pre-treated with exendin-4 and high glucose (Ex-HG), which were taken up by normal HK-2 cells, resulted in decreased levels of FN and Col-I compared with EVs from HK-2 cells pre-treated with HG alone. Furthermore, we found that pretreatment with HG and exendin-4 may have contributed to a decrease in miR-192 in both HK-2 cells and EVs in a p53-dependent manner. Finally, we demonstrated that the amelioration of renal fibrosis by exendin-4 occurred through a miR-192-GLP1R pathway, indicating a new pathway by which exendin-4 regulates GLP1R. The results of this study suggest that exendin-4 inhibits the transfer of EV miR-192 from HG-induced renal tubular epithelial cells to normal cells, thus inhibiting GLP1R downregulation and protecting renal cells. This study reports a new mechanism by which exendin-4 exerts a protective effect against DKD.
Yan-Lin Yang,Meng Xue,Yijie Jia,Fang Hu,Zongji Zheng,Ling Wang,Ze-Kun Si,Yaoming Xue 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-
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.