Lithium preserves peritoneal membrane integrity by suppressing mesothelial cell αB-crystallin

• Published in: Science translational medicine 2021-08, Vol.13 (608)
• Main Authors: Herzog, Rebecca, Sacnun, Juan Manuel, González-Mateo, Guadalupe, Bartosova, Maria, Bialas, Katarzyna, Wagner, Anja, Unterwurzacher, Markus, Sobieszek, Isabel J., Daniel-Fischer, Lisa, Rusai, Krisztina, Pascual-Antón, Lucía, Kaczirek, Klaus, Vychytil, Andreas, Schmitt, Claus Peter, López-Cabrera, Manuel, Alper, Seth L., Aufricht, Christoph, Kratochwill, Klaus
• Format: Article
• Language: English
• Subjects: Angiogenesis; Cell activation; Cell death; Cell injury; Cell survival; Crystallin; Cytotoxicity; Fibrosis; Homeostasis; Lithium; Lithium chloride; Mesenchyme; Patients; Pediatrics; Peritoneal dialysis; Peritoneum; Phenotypes; Preservation; Proteomics; Therapeutic targets; Vascular endothelial growth factor
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aaz9705

Lithium added to peritoneal dialysis fluid protects mesothelial cells and attenuates peritoneal fibrosis and angiogenesis by reducing αB-crystallin. Peritoneal dialysis (PD) is a cost-effective, home-based alternative to hemodialysis for individuals with end-stage renal disease. However, chronic PD results in peritoneal membrane fibrosis and angiogenesis, limiting the therapy. Herzog and colleagues studied the addition of lithium chloride (LiCl), which has cytoprotective effects, to icodextrin-based PD fluids. They identified αB-crystallin as a target protein and elucidated the mechanism by which αB-crystallin promotes a mesothelial-to-mesenchymal transition. They then tested LiCl supplementation to PD fluid in a mouse model of chronic PD, finding that it decreased αB-crystallin abundance, reduced peritoneal thickening, and decreased mesothelial cell expression of fibrosis markers. These findings suggest that LiCl supplementation might prolong PD therapy in humans. Life-saving renal replacement therapy by peritoneal dialysis (PD) is limited in use and duration by progressive impairment of peritoneal membrane integrity and homeostasis. Preservation of peritoneal membrane integrity during chronic PD remains an urgent but long unmet medical need. PD therapy failure results from peritoneal fibrosis and angiogenesis caused by hypertonic PD fluid (PDF)–induced mesothelial cytotoxicity. However, the pathophysiological mechanisms involved are incompletely understood, limiting identification of therapeutic targets. We report that addition of lithium chloride (LiCl) to PDF is a translatable intervention to counteract PDF-induced mesothelial cell death, peritoneal membrane fibrosis, and angiogenesis. LiCl improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most consistently counter-regulated by LiCl. In vitro and in vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like up-regulation of vascular endothelial growth factor (VEGF), CD31-positive cells, and TGF-β–independent activation of TGF-β–regulated targets. In contrast, αB-crystallin knockdown decreased VEGF expression and early mesothelial-to-mesenchymal transition. LiCl reduced VEGF release and counteracted fibrosis- and angiogenesis-associated processes. αB-crystallin in patient-derived mesothelial cells was sp