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

Y. Kim, C. Li, C. Gu, Y. Fang, E. Tycksen, A. Puri, TA. Pietka, J. Sivapackiam, K. Kidd, SJ. Park, BG. Johnson, S. Kmoch, JS. Duffield, AJ. Bleyer, ME. Jackrel, F. Urano, V. Sharma, M. Lindahl, YM. Chen

. 2023 ; 14 (1) : 6493. [pub] 20231014

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc24001048

Grantová podpora
R03 DK106451 NIDDK NIH HHS - United States
P30 DK079337 NIDDK NIH HHS - United States
R21 DK131557 NIDDK NIH HHS - United States
R01 DK105056 NIDDK NIH HHS - United States
P30 DK020579 NIDDK NIH HHS - United States
P30 DK114857 NIDDK NIH HHS - United States
K08 DK089015 NIDDK NIH HHS - United States

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.

Citace poskytuje Crossref.org

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