A14340 Endothelial dysfunction exacerbates renal tubular cell injury through inflammasome activation in hypertensive model mice

Abstract

Objectives: Hypertension causes vascular endothelial dysfunction. Inflammasome activation plays an important role in the development of kidney disease. However the relationship between endothelial function and inflammasome activation is unknown. In this study, we focused on nitric oxide (NO) as a regulator of inflammasome activation. The hypothesis was that endothelium-derived NO would inhibit inflammasome activation and control chronic inflammation in the hypertensive kidney diseases. Methods: Aldosterone (Ald) was continuously administered to wild-type mice (WT) and endothelial NO synthase-knockout (eNOS KO) mice for 4 weeks. To detect inflammasome activation, bone marrow-derived macrophages (BMDMs) were primed with LPS. After LPS priming, the BMDMs were stimulated with ATP to activate the NLRP3 inflammasome. BMDMs were simultaneously primed with GSNO. To determine the role of inflammasome activation in endothelial dysfunction, eNOS/ASC double KO mice (eNOS/ASC DKO) were generated and treated with Ald. Results: The expression of NLRP3 inflammasome-related genes was much higher in the eNOS KO-Ald group than WT-Ald group. Tubular injury and fibrosis were accelerated in the eNOS KO-Ald group as compared with the WT-Ald group. ATP stimulation and LPS priming caused NLRP3 inflammasome-dependent cell death and interleukin-1β (IL-1β) secretion, and GSNO inhibited IL-1β secretion. These data suggested that NO suppressed NLRP3 inflammasome activation directly in macrophages. Ald treatment resulted in a significant increase in the expression of inflammasome-related genes, in addition to increased tubular injury and fibrosis. In contrast, these changes were significantly suppressed in the eNOS/ASC DKO group. Conclusion: NO derived from eNOS inhibited inflammasome activation in an Ald-induced hypertensive model.