MANF clears mutant uromodulin in human kidney organoids of autosomal dominant tubulointerstitial kidney disease
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.
Authors
- Srikanth Singamaneni (ORCID: https://orcid.org/0000-0002-7203-2613)
- Chang Li (ORCID: https://orcid.org/0000-0002-3267-1859)
- Kendrah Kidd (ORCID: https://orcid.org/0000-0003-3771-0949)
- Eric Tycksen (ORCID: https://orcid.org/0000-0001-6362-0141)
- Yili Fang (ORCID: https://orcid.org/0000-0002-8771-3059)
- Ying Maggie Chen (ORCID: https://orcid.org/0000-0003-0994-8925)
- Zhao Sun (ORCID: https://orcid.org/0000-0003-0763-7963)
- Maria Lindahl (ORCID: https://orcid.org/0000-0002-5674-8830)
- Y. M. Wang
- AJ Bleyer
- Chenjian Gu
- Kendrah Kidd
- Gayathri Kondepati
- Jun Liu
- Fumihiko Urano
Institutions
- University of Helsinki (FI)
- The University of Texas at Dallas (US)
- Washington University in St. Louis (US)
- Helsinki Institute of Physics (FI)
- Shanghai First People's Hospital (CN)
- Advanced Genomic Technology (United States) (US)
- Wake Forest University (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-08-25
- DOI
- https://doi.org/10.1172/jci205631
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Heart Association
- American Society of Nephrology
- Center for Selective C-H Functionalization, National Science Foundation
- Academy of Finland
- Diabetestutkimussäätiö
- National Center for Research Resources
- Congressionally Directed Medical Research Programs