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Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy

Disruption of lysosomal homeostasis contributes to the tubulopathy of diabetic nephropathy; however, its underlying mechanisms remain unclear. Herein, we report that decreased activity of transcription factor EB (TFEB) is responsible for the disturbed lysosome biogenesis and clearance in this pathol...

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Autores principales: Wang, Shujun, Jing, Kaipeng, Wu, Hongluan, Li, Xiaoyu, Yang, Chen, Li, Tingting, Tang, Haoxuan, Zou, Ting, She, Yao, Liu, Hua-feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786470/
https://www.ncbi.nlm.nih.gov/pubmed/35082964
http://dx.doi.org/10.1155/2022/2812493
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author Wang, Shujun
Jing, Kaipeng
Wu, Hongluan
Li, Xiaoyu
Yang, Chen
Li, Tingting
Tang, Haoxuan
Zou, Ting
She, Yao
Liu, Hua-feng
author_facet Wang, Shujun
Jing, Kaipeng
Wu, Hongluan
Li, Xiaoyu
Yang, Chen
Li, Tingting
Tang, Haoxuan
Zou, Ting
She, Yao
Liu, Hua-feng
author_sort Wang, Shujun
collection PubMed
description Disruption of lysosomal homeostasis contributes to the tubulopathy of diabetic nephropathy; however, its underlying mechanisms remain unclear. Herein, we report that decreased activity of transcription factor EB (TFEB) is responsible for the disturbed lysosome biogenesis and clearance in this pathological process. This was confirmed by the findings that insufficient lysosomal replenishment and damaged lysosomal clearance coincided with TFEB inactivation, which was mediated by mTOR hyperactivation in the renal tubular epithelial cells (TECs) of diabetic nephropathy. Furthermore, either TFEB overexpression or pharmacological activation of TFEB enhanced lysosomal clearance via promoting lysosomal biogenesis and protected TECs by reducing apoptosis in vitro. In addition, pharmacological activation of TFEB attenuated renal tubule injury, apoptosis, and inflammation in db/db mice. In conclusion, diabetes-induced mTOR activation represses TFEB function, thereby perturbing lysosomal homeostasis through impairing lysosomal biogenesis and clearance in TECs. Moreover, TFEB activation protects TECs from diabetic injuries via restoring lysosomal homeostasis.
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spelling pubmed-87864702022-01-25 Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy Wang, Shujun Jing, Kaipeng Wu, Hongluan Li, Xiaoyu Yang, Chen Li, Tingting Tang, Haoxuan Zou, Ting She, Yao Liu, Hua-feng Oxid Med Cell Longev Research Article Disruption of lysosomal homeostasis contributes to the tubulopathy of diabetic nephropathy; however, its underlying mechanisms remain unclear. Herein, we report that decreased activity of transcription factor EB (TFEB) is responsible for the disturbed lysosome biogenesis and clearance in this pathological process. This was confirmed by the findings that insufficient lysosomal replenishment and damaged lysosomal clearance coincided with TFEB inactivation, which was mediated by mTOR hyperactivation in the renal tubular epithelial cells (TECs) of diabetic nephropathy. Furthermore, either TFEB overexpression or pharmacological activation of TFEB enhanced lysosomal clearance via promoting lysosomal biogenesis and protected TECs by reducing apoptosis in vitro. In addition, pharmacological activation of TFEB attenuated renal tubule injury, apoptosis, and inflammation in db/db mice. In conclusion, diabetes-induced mTOR activation represses TFEB function, thereby perturbing lysosomal homeostasis through impairing lysosomal biogenesis and clearance in TECs. Moreover, TFEB activation protects TECs from diabetic injuries via restoring lysosomal homeostasis. Hindawi 2022-01-12 /pmc/articles/PMC8786470/ /pubmed/35082964 http://dx.doi.org/10.1155/2022/2812493 Text en Copyright © 2022 Shujun Wang et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Wang, Shujun
Jing, Kaipeng
Wu, Hongluan
Li, Xiaoyu
Yang, Chen
Li, Tingting
Tang, Haoxuan
Zou, Ting
She, Yao
Liu, Hua-feng
Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy
title Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy
title_full Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy
title_fullStr Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy
title_full_unstemmed Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy
title_short Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy
title_sort activation of transcription factor eb alleviates tubular epithelial cell injury via restoring lysosomal homeostasis in diabetic nephropathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786470/
https://www.ncbi.nlm.nih.gov/pubmed/35082964
http://dx.doi.org/10.1155/2022/2812493
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