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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F23%3A10472549" target="_blank" >RIV/00216208:11110/23:10472549 - isvavai.cz</a>

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=9GIobHCUGa" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=9GIobHCUGa</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-023-42154-0" target="_blank" >10.1038/s41467-023-42154-0</a>

Result language

angličtina

Original language name

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

Original language 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. Autosomal dominant tubulointerstitial kidney disease (ADTKD) due to uromodulin mutations is a hereditary kidney disease causing renal fibrosis. Here, the authors show that mesencephalic astrocyte-derived neurotrophic factor can improve defective autophagy/mitophagy and decrease renal scarring in ADTKD.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30101 - Human genetics

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nature Communications

ISSN

2041-1723

e-ISSN

2041-1723

Volume of the periodical

14

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

22

Pages from-to

6493

UT code for WoS article

001095513800023

EID of the result in the Scopus database

2-s2.0-85174244106