Targeting STING in experimental peritoneal damage: a novel approach in peritoneal dialysis therapy

Abstract

Peritoneal dialysis (PD) is a widely used kidney replacement therapy for end-stage kidney disease (ESKD) patients. However, long-term exposure to PD fluids (PDF) can lead to peritoneal membrane (PM) damage, causing ultrafiltration failure and thus PD discontinuation. Investigating the molecular mechanisms underlying this damage is crucial for identifying new therapeutic targets to mitigate peritoneal deterioration in PD patients. Therefore, in this work we study the role of STING in peritoneal inflammation and fibrosis. To this aim, we performed different preclinical mouse models of peritoneal inflammation, fibrosis, and adhesions. In a chlorhexidine gluconate (CHX)-induced inflammation model, we found changes in the peritoneal transcriptomic profile, and cytosolic DNA-sensing signaling was one of the most enriched KEGG pathways. STING, as a conspicuous member of this pathway, was upregulated in CHX-and PDF-exposed mice, and in peritoneal biopsies from PD patients. STING genetic deficiency diminished peritoneal inflammation, by downregulating inflammatory gene expression, preventing NF-{kappa}B pathway activation, and decreasing cell infiltration, in early (10 days) and advanced (30 days) stages of the CHX model. STING absence also decreased PM thickness and fibrosis in the advanced CHX model, reduced adhesion scores in a post-surgical intra-abdominal adhesion model, and decreased inflammation in an S. epidermidis-induced peritonitis model. Furthermore, pharmacological inhibition of STING with C-176 decreased inflammation and macrophage-mediated mesothelial-to-mesenchymal transition in cultured mesothelial cells, and reduced CHX-induced PM thickness and inflammation in mice. Altogether, these findings highlight STING as a key mediator of peritoneal damage and suggest it may be a novel therapeutic target for preventing PD-associated peritoneal deterioration.