Journal of Clinical InvestigationGeneticsPeer-reviewed journal article
MANF Clears Mutant Uromodulin in Human Kidney Organoids of Autosomal Dominant Tubulointerstitial Kidney Disease
Chenjian Gu, Yili FangiD, Y. M. Wang, Eric TyckseniD, Gayathri Kondepati, Chuang Li, Kendrah O. KiddiD, Jun Liu, Fumihiko UranoiD, Maria LindahliD, Anthony J. BleyeriD, Srikanth SingamaneniiD, Zhao Qing SuniD, Ying Maggie CheniD
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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