NLRP3 Inflammasome Mediates Aldosterone-Induced Vascular Damage

Background —Inflammation is a key feature of aldosterone-induced vascular damage and dysfunction, but molecular mechanisms by which aldosterone triggers inflammation remain unclear. The NLRP3 inflammasome is a pivotal immune sensor that recognizes endogenous danger signals triggering sterile inflammation. Methods —We analyzed vascular function and inflammatory profile of wild-type (WT), NLRP3 knockout (NLRP3-/-), Caspase-1 knockout (Casp-1-/-) and IL-1 receptor knockout (IL-1R-/-) mice, treated with vehicle or aldosterone (600 ug/kg/day for 14 days, via osmotic mini-pump) while receiving 1% saline to drink. Results —Here we show that NLRP3 inflammasome plays a central role in aldosterone-induced vascular dysfunction. Chronic infusion of aldosterone in mice resulted in elevation of plasma interleukin-1β (IL-1β) levels as well as vascular abnormalities. Mice lacking the IL-1β receptor (IL-1R) or inflammasome components, NLRP3 and caspase-1, were protected from aldosterone-induced vascular damage. In vitro , aldosterone stimulated NLRP3-dependent IL-1β secretion by bone marrow-derived macrophages, by activating NF-kB signaling and reactive oxygen species generation. Moreover, chimeric mice reconstituted with NLRP3-deficient hematopoietic cells showed that NLRP3 in immune cells mediates aldosterone-induced vascular damage. In addition, aldosterone increased the expression of NLRP3, active caspase-1 and mature-IL-1β in human peripheral blood mononuclear cells (PBMC). Hypertensive patients, with hyperaldosteronism or normal levels of aldosterone, exhibited increased activity of NLRP3 inflamassome, suggesting that the effect of hyperaldosteronism on the inflammasome may be mediated through high blood pressure. Conclusions —Together, these data demonstrate that NLRP3 inflammasome, via activation of IL-1 receptor, is critically involved in the deleterious vascular effects of aldosterone, placing NLRP3 as a potential target for therapeutic interventions in conditions with high aldosterone levels.