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

Abstract

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 specifically up-regulated in response to PDF and increased in peritoneal mesothelial cells from biopsies from pediatric patients undergoing PD, correlating with markers of angiogenesis and fibrosis. LiCl-supplemented PDF promoted morphological preservation of mesothelial cells and the submesothelial zone in a mouse model of chronic PD. Thus, repurposing LiCl as a cytoprotective PDF additive may offer a translatable therapeutic strategy to combat peritoneal membrane deterioration during PD therapy.

Proteome-Wide Differential Effects of Peritoneal Dialysis Fluid Properties in an In Vitro Human Endothelial Cell Model

“…We have previously shown that the addition of cytoprotective additives to PD fluid is a valid strategy to ameliorate the damage caused by PD fluids to peritoneal cells [ 11 , 18 , 23 , 24 , 25 , 26 ]. Alanyl-glutamine (AlaGln) has been described to counteract oxidative stress, so we next tested if it can ameliorate the observed effects of exposure of endothelial cells when added to double-chamber fluid (neutral pH).…”

“…PD introduces well-described vascular damage in the peritoneal membrane resembling diabetic vasculopathies [ 9 , 11 , 12 ]. The endothelial cells of these vessels function as the actual filter that regulates the peritoneal fluid transport during PD [ 6 ].…”

“…The endothelial cells of these vessels function as the actual filter that regulates the peritoneal fluid transport during PD [ 6 ]. Comprehensive analysis of common and differential molecular alterations induced by the different available PD fluids and their specific properties has been extensively conducted in mesothelial cells but is missing for endothelial cells [ 5 , 9 , 10 , 11 , 12 , 13 ]. In endothelial cells, only a few selected individual parameters have been analyzed following PD fluid exposure, but a holistic untargeted analysis to decipher molecular changes has not been performed [ 5 , 14 , 15 , 16 , 17 ].…”

Role of Peritoneal Mesothelial Cells in the Progression of Peritoneal Metastases

“…PMCs play important roles in pathological conditions, such as peritoneal dialysis dysfunction [ 21 ], intra-abdominal adhesions [ 22 ], peritoneal inflammation, peritoneal tumor dissemination [ 23 ], and endometriosis [ 24 ]. PMCs also play key roles in dynamic regulation processes such as peritoneal repair [ 25 ], scarring [ 26 ], the regulation of macrophage migration [ 27 ], and the promotion of coagulation [ 25 , 28 ], including the formation of fibrin and the promotion of fibrinolysis [ 29 , 30 ].…”

A Meta-Analysis of Human Transcriptomics Data in the Context of Peritoneal Dialysis Identifies Novel Receptor-Ligand Interactions as Potential Therapeutic Targets

“…High-throughput omics technologies such as microarrays, RNA-sequencing, or proteomics methods allow for simultaneous measurements of thousands of molecular features and support elucidation of dysregulated processes in diseases along with the identification of molecular biomarkers and novel drug targets. A combined analysis of transcriptomics and proteomics data in the context of PD recently led to the identification of the beneficial impact of lithium on peritoneal membrane integrity, thus demonstrating that an integrated analysis of Omics data can also lead to novel therapeutic strategies [3]. A number of individual Omics studies in the context of PD have been published in the past couple of years investigating the impact of different dialysis fluids or different additives on patient outcome and the discovery of associated molecular pathways [4,5].…”