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

Yeawon Kim, Chuang Li, Chenjian Gu, Yili Fang, Eric Tycksen, Anuradhika Puri, Terri A. Pietka, Jothilingam Sivapackiam, Kendrah Kidd, Sun-Ji Park, Bryce G. Johnson, Stanislav Kmoch, Jeremy S. Duffield, Anthony J. Bleyer, Meredith E. Jackrel, Fumihiko Urano, Vijay Sharma, Maria Lindahl and Ying Maggie Chen ()
Additional contact information
Yeawon Kim: Washington University School of Medicine
Chuang Li: Washington University School of Medicine
Chenjian Gu: Washington University School of Medicine
Yili Fang: Washington University School of Medicine
Eric Tycksen: Washington University School of Medicine
Anuradhika Puri: Washington University
Terri A. Pietka: Washington University School of Medicine
Jothilingam Sivapackiam: Washington University School of Medicine
Kendrah Kidd: Wake Forest University School of Medicine
Sun-Ji Park: Washington University School of Medicine
Bryce G. Johnson: Pfizer Worldwide Research and Development, Inflammation & Immunology
Stanislav Kmoch: Wake Forest University School of Medicine
Jeremy S. Duffield: Prime Medicine, Inc
Anthony J. Bleyer: Wake Forest University School of Medicine
Meredith E. Jackrel: Washington University
Fumihiko Urano: Washington University School of Medicine
Vijay Sharma: Washington University School of Medicine
Maria Lindahl: HiLIFE, University of Helsinki
Ying Maggie Chen: Washington University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract 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.

Date: 2023
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-42154-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42154-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-42154-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().