Beyond Aquaporins: Tamoxifen Preserves Collecting Duct Epithelial Homeostasis in Lithium-Induced Nephrogenic Diabetes Insipidus
5 affiliations
- 1Department of Biosciences Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy
- 2Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- 3Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
- 4Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark
- 5Department of Renal Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
Abstract
Lithium is widely used to treat psychiatric disorders, including bipolar disorder. However, long-term lithium therapy is frequently associated with acquired nephrogenic diabetes insipidus (NDI), a disorder characterized by impaired urinary concentrating ability and excessive water loss. Tamoxifen (TAM), a selective estrogen receptor modulator, has previously been shown to alleviate lithium-induced NDI by restoring AQP2 and AQP3 expression. Here, we investigated whether necroptosis-related signaling, primary cilium remodeling, and epithelial–mesenchymal transition (EMT)-like changes contribute to lithium-induced collecting duct alterations and whether TAM modulates these responses. Using complementary in vitro, ex vivo, and in vivo approaches, we found that lithium significantly reduced the expression of the necroptosis-related proteins receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), whereas TAM prevented their downregulation. Lithium also induced primary cilium elongation and promoted EMT-like changes, characterized by reduced E-cadherin and increased vimentin expression, which were attenuated by TAM. Collectively, these findings demonstrate that lithium profoundly alters collecting duct epithelial homeostasis by modulating the abundance of necroptosis-related proteins, primary cilium morphology, and epithelial phenotype. The ability of TAM to counteract these alterations indicates that its protective effects extend beyond aquaporin regulation, supporting its potential as a therapeutic strategy for lithium-induced NDI.
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BibTeX
@article{centrone2026beyond,
title = {{Beyond Aquaporins: Tamoxifen Preserves Collecting Duct Epithelial Homeostasis in Lithium-Induced Nephrogenic Diabetes Insipidus}},
author = {Mariangela Centrone and Ines Angelini and Mariagrazia D’Agostino and Annarita Di Mise and Barbara Barile and Grazia Paola Nicchia and Giampaolo Morciano and Stine Julie Tingskov and Xabier Sørtvedt and Birgitte Mønster Christensen and Marianna Ranieri and Giovanna Valenti and Rikke Nørregaard and Grazia Tamma},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15211953},
url = {https://www.mdpi.com/2073-4409/15/21/1953},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Beyond Aquaporins: Tamoxifen Preserves Collecting Duct Epithelial Homeostasis in Lithium-Induced Nephrogenic Diabetes Insipidus
AU - Mariangela Centrone
AU - Ines Angelini
AU - Mariagrazia D’Agostino
AU - Annarita Di Mise
AU - Barbara Barile
AU - Grazia Paola Nicchia
AU - Giampaolo Morciano
AU - Stine Julie Tingskov
AU - Xabier Sørtvedt
AU - Birgitte Mønster Christensen
AU - Marianna Ranieri
AU - Giovanna Valenti
AU - Rikke Nørregaard
AU - Grazia Tamma
PY - 2026
DA - 2026/10/27
JO - Cells
DO - 10.3390/cells15211953
UR - https://www.mdpi.com/2073-4409/15/21/1953
AB - Lithium is widely used to treat psychiatric disorders, including bipolar disorder. However, long-term lithium therapy is frequently associated with acquired nephrogenic diabetes insipidus (NDI), a disorder characterized by impaired urinary concentrating ability and excessive water loss. Tamoxifen (TAM), a selective estrogen receptor modulator, has previously been shown to alleviate lithium-induced NDI by restoring AQP2 and AQP3 expression. Here, we investigated whether necroptosis-related signaling, primary cilium remodeling, and epithelial–mesenchymal transition (EMT)-like changes contribute to lithium-induced collecting duct alterations and whether TAM modulates these responses. Using complementary in vitro, ex vivo, and in vivo approaches, we found that lithium significantly reduced the expression of the necroptosis-related proteins receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), whereas TAM prevented their downregulation. Lithium also induced primary cilium elongation and promoted EMT-like changes, characterized by reduced E-cadherin and increased vimentin expression, which were attenuated by TAM. Collectively, these findings demonstrate that lithium profoundly alters collecting duct epithelial homeostasis by modulating the abundance of necroptosis-related proteins, primary cilium morphology, and epithelial phenotype. The ability of TAM to counteract these alterations indicates that its protective effects extend beyond aquaporin regulation, supporting its potential as a therapeutic strategy for lithium-induced NDI.
SN - 2073-4409
ER -