INFLUENCE OF THE DJ-1/NRF2 PATHWAY AND NLRP3 INFLAMMASOME ACTIVATION ON BLOOD PRESSURE REGULATION INDUCED BY A HIGH-SALT DIET

Objective: High salt intake is a major contributor to the development and exacerbation of hypertension, partly by inducing an inflammatory response through immune cell dysfunction. Inflammasomes, key components of the innate immune response, may influence blood pressure regulation. The renal DJ-1 protein is known for its antioxidant and anti-inflammatory properties. To explore novel pharmacological applications, we developed ND-13, a peptide consisting of 13 highly conserved amino acids derived from the DJ-1 sequence. In this study, we investigated the effects of ND-13 and MCC950, a specific NLRP3 inflammasome inhibitor, on blood pressure regulation in C57BL/6 mice subjected to a high-salt diet. Design and method: C57BL/6 mice were fed a high-salt diet for one week and treated with ND-13 or MCC950, an NLRP3 inflammasome inhibitor. Subsequently, the mice were analyzed for gene expression by qPCR, immune staining of renal immune cells, Sirius Red and Periodic Acid-Schiff (PAS) staining of renal tissue, and inflammasome activity in peritoneal cells. Results: One week of high salt intake resulted in an increase in blood pressure, which was prevented by both ND-13 and MCC950 treatments. Notably, renal expression of inflammatory genes, immune cell infiltration, and renal collagen deposition were not observed in the high-salt diet group. However, proteinuria increased significantly, accompanied by tubular protein deposits detected via PAS staining which is prevented by both ND-13 and MCC950 treatments. Peritoneal macrophages isolated from high-salt diet mice exhibited enhanced IL-1B release upon LPS+ATP stimulation, suggesting activation of the NLRP3 inflammasome under these conditions. Treatment with ND-13 and MCC950 normalized this activity. Furthermore, ND-13 reduced IL-1B mRNA expression in peritoneal macrophages.Conclusions: Our findings highlight the critical role of the NLRP3 inflammasome in salt-sensitive blood pressure regulation and suggest that ND-13 may serve as a potential therapeutic agent for preventing hypertension and associated inflammatory alterations induced by high salt intake.