Regulation of Renal Sodium Excretion by Medullary NLRP3 Inflammasome Activation beyond Turning on Inflammation

Abstract

NLRP3 inflammasomes were found abundant in the renal medulla and their activation altered the renal function and increased the salt sensitivity of arterial blood pressure (AP). The present study further explored the mechanisms mediating the effects of NLRP3 inflammasomes on renal excretory function, which may be independent of typical inflammatory response. In anesthetized mice, intramedullary infusion of NLRP3 inflammasome activators, monosodium urate (MSU) or ATP induced significant decreases in sodium excretion by more than 50% and medullary blood flow (MBF) by 15% without changes in mean AP and renal cortical blood flow (CBF). Pre‐infusion of caspase‐1 inhibitor, Ac‐YVAD‐CMK abolished MSU or ATP‐induced decreases in renal sodium excretion and MBF. By co‐immunoprecipitation analysis, inflammasome component proteins ASC, caspase‐1 and NLRP3 were found to interact more actively in the renal medulla with infusion of MSU or ATP compared to control mice, suggesting enhanced inflammasome formation. Moreover, the caspase‐1 activity was shown significantly increased by 1.5 folds in the renal medulla receiving MSU or ATP, which was accompanied by a 20% increase in local IL‐1β level. Interestingly, SOD mimetic TEMPOL was found to not only block increases in O2− levels induced by MSU or ATP, but also prevent caspase‐1 activation and IL‐1β production. Correspondingly, MSU or ATP‐induced reduction of sodium excretion and renal MBF were reversed by TEMPOL. In additional group of mice, direct infusion of IL‐1β (10 ng/kg/min) into the renal medulla mimicked the effects of MSU or ATP, reducing sodium excretion by 35% and MBF by 10%. Taken together, our results support the view that beyond turning on inflammation, activation of NLRP3 inflammasomes in the renal medulla has direct effects on renal vessels and tubules to induce sodium retention, ultimately resulting in hypertension (Supported by NIH grants HL057244, HL‐75316 and DK54927).