Beyond Aquaporins: Tamoxifen Preserves Collecting Duct Epithelial Homeostasis in Lithium-Induced Nephrogenic Diabetes Insipidus

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.