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Abstract: FR-PO513

Tamoxifen Attenuates the Lithium-Induced Decrease in Necroptosis in Renal-Collecting Duct Cells

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

  • 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Centrone, Mariangela, Universita degli Studi di Bari Aldo Moro, Bari, Italy
  • D'Agostino, Mariagrazia, Universita degli Studi di Bari Aldo Moro, Bari, Italy
  • Angelini, Ines, Universita degli Studi di Bari Aldo Moro, Bari, Italy
  • Di Mise, Annarita, Universita degli Studi di Bari Aldo Moro, Bari, Italy
  • Ranieri, Marianna, Universita degli Studi di Bari Aldo Moro, Bari, Italy
  • Tingskov, Stine Julie, Aarhus Universitetshospital, Aarhus, Denmark
  • Norregaard, Rikke, Aarhus Universitetshospital, Aarhus, Denmark
  • Valenti, Giovanna, Universita degli Studi di Bari Aldo Moro, Bari, Italy
  • Tamma, Grazia, Universita degli Studi di Bari Aldo Moro, Bari, Italy
Background

Lithium is recommended for bipolar disease, but it generally displays adverse effects including chronic kidney disease and acquired nephrogenic diabetes insipidus, a disorder characterized by a defective renal concentrating ability that leads to massive water loss. Several data demonstrated that tamoxifen attenuates the development of lithium-induced NDI by modulating AQP2 and AQP3 expression and function. Recent studies revealed that lithium promotes proliferation and autophagy in renal cells. Here, we identify the heat-shock-protein 90 (HSP90) as a novel player involved in signaling activated by lithium treatment and leading to the inhibition of cell necroptosis. Inhibition of HSP90 may lead to conformational changes and degradation of RIP3 which is a key protein promoting necroptosis via MLKL.

Methods

Renal collecting duct MCD4 cells were used as an experimental model. Western Blotting analysis was applied to evaluate the expression and function of proteins.

Results

Exposure of MCD4 cells to lithium (10mM for 48 hours) significantly reduced the expression of HSP90, RIP3, and MLKL. A relevant decrease in phosphorylated MLKL was also detected. A decrease in the expression of BID and an increase of beclin, selective markers of apoptosis and autophagy respectively, were found as well. The effect of tamoxifen on necroptosis was evaluated considering that tamoxifen enhances the client activity of HSP90. Notably, either tamoxifen or IP6, a known activator of necroptosis, reversed the effect of lithium on HSP90 and RIP3 expression. Importantly, preliminary in vivo data showed that lithium decreased the expression of RIP3. By contrast, tamoxifen reversed the lithium-induced RIP3 reduction.

Conclusion

Together, these findings revealed for the first time that exposure of renal collecting duct cells to lithium resulted in a significant reduction in the expression level of selective markers of necroptosis possibly through HSP90 inhibition. Treatment with tamoxifen counteracts the lithium-induced downregulation of HSP90 and RIP3.

Funding

  • Government Support – Non-U.S.