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

Area of Science:

• Nephrology
• Regenerative Medicine
• Biomaterials Science

Background:

• Peritoneal dialysis (PD) therapy is crucial for renal replacement but is limited by progressive peritoneal membrane damage.
• This damage, characterized by fibrosis and angiogenesis, stems from cytotoxicity induced by hypertonic PD fluid (PDF).
• The underlying mechanisms of PDF-induced mesothelial cell injury are not fully understood, hindering therapeutic development.

Purpose of the Study:

• To investigate the potential of lithium chloride (LiCl) as a therapeutic additive to PDF to preserve peritoneal membrane integrity.
• To elucidate the role of αB-crystallin in PDF-induced mesothelial cell injury, fibrosis, and angiogenesis.
• To evaluate the efficacy of LiCl-supplemented PDF in preclinical models and patient-derived cells.

Main Methods:

• Transcriptomic and proteomic analyses of mesothelial cells exposed to PDF.
• In vitro and in vivo studies involving overexpression and knockdown of αB-crystallin.
• Assessment of LiCl effects on cell survival, fibrosis markers, angiogenesis, and mesothelial-to-mesenchymal transition.
• Analysis of patient-derived mesothelial cells and biopsies.
• Evaluation of LiCl-supplemented PDF in a mouse model of chronic PD.

Main Results:

• LiCl demonstrated dose-dependent cytoprotective effects on mesothelial cells and counteracted PDF-induced fibrosis and angiogenesis.
• αB-crystallin was identified as a key mediator, with its overexpression promoting fibrotic and angiogenic phenotypes.
• LiCl reduced αB-crystallin levels, inhibited VEGF release, and preserved peritoneal membrane morphology in vivo.
• αB-crystallin was upregulated in patient-derived cells and biopsies, correlating with fibrosis and angiogenesis markers.

Conclusions:

• LiCl is a promising cytoprotective agent that can be repurposed as a PDF additive to mitigate peritoneal membrane deterioration.
• Targeting αB-crystallin may offer a novel therapeutic strategy to improve long-term PD therapy outcomes.
• This intervention holds potential to extend the duration and effectiveness of life-saving peritoneal dialysis.