Dulaglutide markedly prevents peritoneal fibrosis in a rodent model of chronic kidney disease: Insights into the pathogenesis

Peritoneal fibrosis (PF) is a major complication of long-term peritoneal dialysis, leading to ultrafiltration failure and technique dropout, highlighting the urgent need for therapies that can preserve peritoneal membrane function and longevity. The present study evaluated the effectiveness of dulaglutide in preserving the functional integrity and durability of the peritoneum while inhibiting PF. <i>In vitro</i> Met-5A cells showed significant upregulation of inflammatory, oxidative stress, intracellular and mitochondrial reactive oxygen species (ROS), fibrotic, intracellular cytoskeletal, apoptotic and epithelial-mesenchymal transition (EMT) biomarkers, and dipeptidyl peptidase 4 (DPP4), following stimulation with a uremic toxin (p-Cresol), PF inducer [chlorhexidine gluconate (CG)] or endotoxin [lipopolysaccharide (LPS)]. Notably, these effects were significantly suppressed by dulaglutide or TGF-β/DPP4 double silencing. Furthermore, cell viability and glucagon-like peptide 1 (GLP-1) expression displayed an opposite pattern to ROS among the groups. Sprague-Dawley rats were divided into the following groups: i) Sham control (SC); ii) chronic kidney disease (CKD); iii) CKD + CG (mimicking renal failure and PF); and iv) CKD + CG + dulaglutide, and were euthanized by day 42. At this time point, the highest levels of peritoneal protein expression levels of oxidative stress (NOX-1, NOX-2 and DPP4), inflammation (NF-κB and TNF-α), angiogenesis (CD31 and von Willebrand factor) and EMT (TGF-β, Snail, β-catenin, vimentin, phosphorylated-Smad3, α-smooth muscle actin, collagen I, N-cadherin and fibronectin) factors; and cellular expression levels of fibrosis and inflammation markers, were observed in the CKD + CG group, the lowest were detected in the SC group, and the levels were significantly reduced in the CKD + CG + dulaglutide group compared with those in the CKD group. Furthermore, the expression levels of antioxidant proteins (nuclear factor erythroid 2-related factor 2, NAD(P)H quinone oxidoreductase 1 and GLP-1 receptor) exhibited an opposite trend to ROS-associated proteins among the groups. Additional Sprague-Dawley rats were categorized into the following groups: i) SC; ii) LPS-induced peritonitis; iii) LPS-induced peritonitis + dulaglutide, and were euthanized by day 5 after peritonitis induction. At this time point, flow cytometry revealed significantly increased levels of inflammatory cells (CD11b/c⁺, myeloperoxidase⁺ and Ly6G⁺ cells) in the circulation and abdominal fluid, and increased peritoneal permeability in the LPS-induced peritonitis group compared with those in the SC group; these levels were significantly reversed in the LPS-induced peritonitis + dulaglutide group. In conclusion, dulaglutide may effectively maintain peritoneal integrity primarily by suppressing inflammation, oxidative stress, EMT and fibrosis.