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Loss of legumain induces premature senescence and mediates aging‐related renal fibrosis
Aging is an independent risk factor for acute kidney injury and subsequent chronic kidney diseases, while the underlying mechanism is still elusive. Here, we found that renal tubules highly express a conserved lysosomal endopeptidase, legumain, which is significantly downregulated with the growing o...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920435/ https://www.ncbi.nlm.nih.gov/pubmed/35195326 http://dx.doi.org/10.1111/acel.13574 |
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author | Wang, Dekun Kang, Lichun Chen, Chuan'ai Guo, Jiasen Du, Lingfang Zhou, Donghui Li, Gang Zhang, Yuying Mi, Xue Zhang, Mianzhi Liu, Shuxia Tan, Xiaoyue |
author_facet | Wang, Dekun Kang, Lichun Chen, Chuan'ai Guo, Jiasen Du, Lingfang Zhou, Donghui Li, Gang Zhang, Yuying Mi, Xue Zhang, Mianzhi Liu, Shuxia Tan, Xiaoyue |
author_sort | Wang, Dekun |
collection | PubMed |
description | Aging is an independent risk factor for acute kidney injury and subsequent chronic kidney diseases, while the underlying mechanism is still elusive. Here, we found that renal tubules highly express a conserved lysosomal endopeptidase, legumain, which is significantly downregulated with the growing of age. Tubule‐specific legumain‐knockout mice exhibit spontaneous renal interstitial fibrosis from the 3rd month. In the tubule‐specific legumain‐knockout mice and the cultured legumain‐knockdown HK‐2 cells, legumain deficiency induces the activation of tubular senescence and thus increases the secretion of profibrotic senescence‐associated cytokines, which in turn accelerates the activation of fibroblasts. Blockage of senescence mitigates the fibrotic lesion caused by legumain deficiency. Mechanistically, we found that silencing down of legumain leads to the elevated lysosome pH value, enlargement of lysosome size, and increase of lysosomal voltage dependent membrane channel proteins. Either legumain downregulation or aging alone induces the activation of nuclear transcription factors EB (TFEB) while it fails to further upregulate in the elderly legumain‐knockdown tubules, accompanied with impaired mitophagy and increased mitochondrial ROS (mtROS) accumulation. Therapeutically, supplementation of exosomal legumain ameliorated fibronectin and collagen I production in an in vitro coculture system of tubular cells and fibroblasts. Altogether, our data demonstrate that loss of legumain in combined with aging dysregulates lysosomal homeostasis, although either aging or legumain deficiency alone induces lysosome adaptation via stimulating lysosomal biogenesis. Consequently, impaired mitophagy leads to mtROS accumulation and therefore activates tubular senescence and boosts the interstitial fibrosis. |
format | Online Article Text |
id | pubmed-8920435 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89204352022-03-18 Loss of legumain induces premature senescence and mediates aging‐related renal fibrosis Wang, Dekun Kang, Lichun Chen, Chuan'ai Guo, Jiasen Du, Lingfang Zhou, Donghui Li, Gang Zhang, Yuying Mi, Xue Zhang, Mianzhi Liu, Shuxia Tan, Xiaoyue Aging Cell Research Articles Aging is an independent risk factor for acute kidney injury and subsequent chronic kidney diseases, while the underlying mechanism is still elusive. Here, we found that renal tubules highly express a conserved lysosomal endopeptidase, legumain, which is significantly downregulated with the growing of age. Tubule‐specific legumain‐knockout mice exhibit spontaneous renal interstitial fibrosis from the 3rd month. In the tubule‐specific legumain‐knockout mice and the cultured legumain‐knockdown HK‐2 cells, legumain deficiency induces the activation of tubular senescence and thus increases the secretion of profibrotic senescence‐associated cytokines, which in turn accelerates the activation of fibroblasts. Blockage of senescence mitigates the fibrotic lesion caused by legumain deficiency. Mechanistically, we found that silencing down of legumain leads to the elevated lysosome pH value, enlargement of lysosome size, and increase of lysosomal voltage dependent membrane channel proteins. Either legumain downregulation or aging alone induces the activation of nuclear transcription factors EB (TFEB) while it fails to further upregulate in the elderly legumain‐knockdown tubules, accompanied with impaired mitophagy and increased mitochondrial ROS (mtROS) accumulation. Therapeutically, supplementation of exosomal legumain ameliorated fibronectin and collagen I production in an in vitro coculture system of tubular cells and fibroblasts. Altogether, our data demonstrate that loss of legumain in combined with aging dysregulates lysosomal homeostasis, although either aging or legumain deficiency alone induces lysosome adaptation via stimulating lysosomal biogenesis. Consequently, impaired mitophagy leads to mtROS accumulation and therefore activates tubular senescence and boosts the interstitial fibrosis. John Wiley and Sons Inc. 2022-02-23 2022-03 /pmc/articles/PMC8920435/ /pubmed/35195326 http://dx.doi.org/10.1111/acel.13574 Text en © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Wang, Dekun Kang, Lichun Chen, Chuan'ai Guo, Jiasen Du, Lingfang Zhou, Donghui Li, Gang Zhang, Yuying Mi, Xue Zhang, Mianzhi Liu, Shuxia Tan, Xiaoyue Loss of legumain induces premature senescence and mediates aging‐related renal fibrosis |
title | Loss of legumain induces premature senescence and mediates aging‐related renal fibrosis |
title_full | Loss of legumain induces premature senescence and mediates aging‐related renal fibrosis |
title_fullStr | Loss of legumain induces premature senescence and mediates aging‐related renal fibrosis |
title_full_unstemmed | Loss of legumain induces premature senescence and mediates aging‐related renal fibrosis |
title_short | Loss of legumain induces premature senescence and mediates aging‐related renal fibrosis |
title_sort | loss of legumain induces premature senescence and mediates aging‐related renal fibrosis |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920435/ https://www.ncbi.nlm.nih.gov/pubmed/35195326 http://dx.doi.org/10.1111/acel.13574 |
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