Abstract
Epithelial–mesenchymal transition (EMT) of renal tubular epithelial cells is one of the potential mechanisms of renal fibrosis, which promotes the development of diabetic nephropathy (DN). However, the molecular mechanisms of EMT remain largely unknown. Tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signaling, and the loss of TSC1 or TSC2 function leads to a spectrum of diseases that underlie abnormalities in cell growth, proliferation, differentiation, and migration. In this study, we investigated the effects of TSC1 on high glucose (HG)-induced EMT of human proximal tubular epithelial HK-2 cells in vitro and renal fibrosis in TSC1−/− and db/db mice. We found that the exposure of HK-2 cells to HG (30 mM) time-dependently decreased TSC1 expression, increased the phosphorylation of mTORC1, P70S6K, and 4E-BP-1, and promoted cell migration, resulting in EMT. Transfection of the cells with TSC1 mimic significantly ameliorated HG-induced EMT of HK-2 cells. The tubules-specific TSC1 knockout mice (TSC1−/−) displayed a significant decline in renal function. TSC1−/− mice, similar to db/db mice, showed greatly activated mTORC1 signaling and EMT process in the renal cortex and exacerbated renal fibrosis. Overexpression of TSC1 through LV-TSC1 transfection significantly alleviated the progression of EMT and renal fibrosis in the renal cortex of db/db mice. Taken together, our results suggest that TSC1 plays a key role in mediating HG-induced EMT, and inhibition of TSC1-regulated mTORC1 signaling may be a potential approach to prevent renal fibrosis in DN.
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13 October 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41401-021-00785-3
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Acknowledgements
The work was supported by the National Natural Science Foundation of China (No. 81473257, 81400741), the Qing Lan project, the Natural Science Foundation of Jiangsu Province (No. BK20151155), the “333” Foundation of Jiangsu Province (No. BRA2015329), the Key Natural Science Foundation of Jiangsu Higher Education Institutions of China (No. 15KJA310005), the Jiangsu Overseas Research & Training Program for University Young & Middle-aged Teachers and Presidents, and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
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XXY designed and supervised the study and revised the paper; QL, YBC, HY, and WWW performed most of the experiments; CCL and LW performed some of the experiments and analyzed part of the data; JW made the figures; LD purchased the reagents.
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Lu, Q., Chen, Yb., Yang, H. et al. Inactivation of TSC1 promotes epithelial-mesenchymal transition of renal tubular epithelial cells in mouse diabetic nephropathy. Acta Pharmacol Sin 40, 1555–1567 (2019). https://doi.org/10.1038/s41401-019-0244-6
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DOI: https://doi.org/10.1038/s41401-019-0244-6
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