Role of NLRP3 activation in salt sensitive blood pressure regulation, effect of ND-13

Abstract

Background and ObjectivesHigh 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 of renal DJ-1 pathway, 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/6J mice on a high-salt diet. MethodsC57BL/6J mice were fed a high-salt diet (HS) for one week and then treated with ND-13 or MCC950, an NLRP3 inflammasome inhibitor. Subsequently, gene expression by qPCR, staining of immune cells, Sirius Red and Periodic Acid-Schiff (PAS) staining were determined in the mice kidneys, as well as the inflammasome activity in peritoneal cells. ResultsOne week of HS resulted increased in blood pressure, that was prevented by both ND-13 and MCC950 treatments. These treatments also prevented the increase in proteinuria that was accompanied by tubular protein deposits. Renal expression of inflammatory genes, immune cell infiltration, and renal collagen deposition were not observed in the HS group. Peritoneal macrophages isolated from HS treated mice exhibited enhanced IL-1{beta} release upon LPS+ATP stimulation, suggesting activation of the NLRP3 inflammasome. Treatment with ND-13 and MCC950 normalized this activity. Furthermore, ND-13 reduced IL-1{beta} mRNA expression in peritoneal macrophages. ConclusionsOur 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 a high salt intake.