Abstract
Upregulation of thrombin receptor protease-activated receptor 1 (PAR-1) is verified to contribute to chronic kidney diseases, including diabetic nephropathy; however, the mechanisms are still unclear. In this study, we investigated the effect of PAR-1 on high glucose-induced proliferation of human glomerular mesangial cells (HMCs), and explored the mechanism of PAR-1 upregulation from alteration of microRNAs. We found that high glucose stimulated proliferation of the mesangial cells whereas PAR-1 inhibition with vorapaxar attenuated the cell proliferation. Moreover, high glucose upregulated PAR-1 in mRNA level and protein expression while did not affect the enzymatic activity of thrombin in HMCs after 48 h culture. Then high glucose induced PAR-1 elevation was likely due to the alteration of the transcription or post-transcriptional processing. It was found that miR-17 family members including miR-17-5p, -20a-5p, and -93-5p were significantly decreased among the eight detected microRNAs only in high glucose-cultured HMCs, but miR-129-5p, miR-181a-5p, and miR-181b-5p were markedly downregulated in both high glucose-cultured HMCs and equivalent osmotic press control compared with normal glucose culture. So miR-20a was selected to confirm the role of miR-17 family on PAR-1 upregulation, finding that miR-20a-5p overexpression reversed the upregulation of PAR-1 in mRNA and protein levels induced by high glucose in HMCs. In summary, our finding indicated that PAR-1 upregulation mediated proliferation of glomerular mesangial cells induced by high glucose, and deficiency of miR-17 family resulted in PAR-1 upregulation.
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The data and materials used during the current study are available from the corresponding author on reasonable request.
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Funding
This study was supported by Medical Science Foundation of Jiangsu Province (H2019007), and National Natural Science Foundation of China (No. 81774248), China.
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Liu YW and Gou LS conceived and designed research. Tang ZZ conducted experiments. An XF contributed new reagents or analytical tools. Tang ZZ and Gu PP analyzed data. Gu PP and Liu YW wrote the manuscript. All authors read and approved the manuscript, and all data were generated in-house and that no paper mill was used.
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Tang, ZZ., Gu, PP., An, XF. et al. Lack of miRNA-17 family mediates high glucose-induced PAR-1 upregulation in glomerular mesangial cells. Naunyn-Schmiedeberg's Arch Pharmacol 395, 77–85 (2022). https://doi.org/10.1007/s00210-021-02184-1
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DOI: https://doi.org/10.1007/s00210-021-02184-1