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.

doi:10.64898/2026.03.02.708095

bioRxiv · 10.64898/2026.03.02.708095

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.

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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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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. MANF Clears Mutant Uromodulin in Human Kidney Organoids of Autosomal Dominant Tubulointerstitial Kidney Disease. https://doi.org/10.64898/2026.03.02.708095

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