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MANF Clears Mutant Uromodulin in Human Kidney Organoids of Autosomal Dominant Tubulointerstitial Kidney Disease

Gu, C.; Fang, Y.; Wang, Y.; Tycksen, E.; Kondepati, G.; Li, C.; Kidd, K.; Liu, J.; Urano, F.; Lindahl, M.; Bleyer, A. J.; Singamaneni, S.; Sun, Z.; Chen, Y. M.

2026-03-02 genetics
10.64898/2026.03.02.708095 bioRxiv
Show abstract

Autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD) is one of the leading hereditary kidney diseases. Currently there is no targeted treatment. To illuminate human relevance of mesencephalic astrocyte-derived neurotrophic factor (MANF)-based therapy, we have established patient induced pluripotent stem cell (iPSC)-derived kidney organoid model carrying UMOD p.H177-R185del, the leading mutation causing ADTKD. We have discovered that MANF can directly bind and repress ER calcium release channel IP3R1, thus enhancing AMPK-induced autophagy in a TRIB3-dependent manner. The therapeutic implication of this finding may well be extended to other protein misfolding diseases.

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