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MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carr...

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Autores principales: Kim, Yeawon, Li, Chuang, Gu, Chenjian, Fang, Yili, Tycksen, Eric, Puri, Anuradhika, Pietka, Terri A., Sivapackiam, Jothilingam, Kidd, Kendrah, Park, Sun-Ji, Johnson, Bryce G., Kmoch, Stanislav, Duffield, Jeremy S., Bleyer, Anthony J., Jackrel, Meredith E., Urano, Fumihiko, Sharma, Vijay, Lindahl, Maria, Chen, Ying Maggie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576802/
https://www.ncbi.nlm.nih.gov/pubmed/37838725
http://dx.doi.org/10.1038/s41467-023-42154-0
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author Kim, Yeawon
Li, Chuang
Gu, Chenjian
Fang, Yili
Tycksen, Eric
Puri, Anuradhika
Pietka, Terri A.
Sivapackiam, Jothilingam
Kidd, Kendrah
Park, Sun-Ji
Johnson, Bryce G.
Kmoch, Stanislav
Duffield, Jeremy S.
Bleyer, Anthony J.
Jackrel, Meredith E.
Urano, Fumihiko
Sharma, Vijay
Lindahl, Maria
Chen, Ying Maggie
author_facet Kim, Yeawon
Li, Chuang
Gu, Chenjian
Fang, Yili
Tycksen, Eric
Puri, Anuradhika
Pietka, Terri A.
Sivapackiam, Jothilingam
Kidd, Kendrah
Park, Sun-Ji
Johnson, Bryce G.
Kmoch, Stanislav
Duffield, Jeremy S.
Bleyer, Anthony J.
Jackrel, Meredith E.
Urano, Fumihiko
Sharma, Vijay
Lindahl, Maria
Chen, Ying Maggie
author_sort Kim, Yeawon
collection PubMed
description Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.
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spelling pubmed-105768022023-10-16 MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice Kim, Yeawon Li, Chuang Gu, Chenjian Fang, Yili Tycksen, Eric Puri, Anuradhika Pietka, Terri A. Sivapackiam, Jothilingam Kidd, Kendrah Park, Sun-Ji Johnson, Bryce G. Kmoch, Stanislav Duffield, Jeremy S. Bleyer, Anthony J. Jackrel, Meredith E. Urano, Fumihiko Sharma, Vijay Lindahl, Maria Chen, Ying Maggie Nat Commun Article Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies. Nature Publishing Group UK 2023-10-14 /pmc/articles/PMC10576802/ /pubmed/37838725 http://dx.doi.org/10.1038/s41467-023-42154-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kim, Yeawon
Li, Chuang
Gu, Chenjian
Fang, Yili
Tycksen, Eric
Puri, Anuradhika
Pietka, Terri A.
Sivapackiam, Jothilingam
Kidd, Kendrah
Park, Sun-Ji
Johnson, Bryce G.
Kmoch, Stanislav
Duffield, Jeremy S.
Bleyer, Anthony J.
Jackrel, Meredith E.
Urano, Fumihiko
Sharma, Vijay
Lindahl, Maria
Chen, Ying Maggie
MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
title MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
title_full MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
title_fullStr MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
title_full_unstemmed MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
title_short MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
title_sort manf stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576802/
https://www.ncbi.nlm.nih.gov/pubmed/37838725
http://dx.doi.org/10.1038/s41467-023-42154-0
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