Abstract 13593: Spironolactone Suppresses the Inflammasome in Aldosterone Induced Renal Dysfunction via Blood Pressure Independent Pathway
Background: The inflammasome is a cytoplasmic multiprotein complex that activates caspase-1, leading to the processing and secretion of the pro-inflammatory cytokines, such as IL-1β,IL-18, and IL-33. Inflammasome plays a major role in innate immunity but also is deeply involved in multiple inflammatory processes including diabetes, atherosclerosis, and chronic kidney disease. Aldosterone induces tubulointerstitial injuries through activation of proinflammatory signaling pathways. Recent reports suggest that activation of inflammasomes is implicated in aldosterone induced inflammatory process. We hypothesized that activation of inflammasomes is involved in inflammatory responses and tubulointerstitial injury induced by aldosterone.
Methods: Seven-week-old male C57BL/6J mice were used. All animals received left uninephrectomy and were given drinking water with 1% NaCl. The mice were divided into the following groups and treated for 4 weeks: (1) vehicle infusion (Cont), (2) aldosterone infusion (Ald; 0.25 mg/kg/day), and (3) Ald and spironolactone (Ald+Spi; 50 mg/kg/day, gavage). Aldosterone or vehicle solution was infused via osmotic pumps. Expression of inflammasome components, apoptosis-associated speck-like protein (ASC), and NOD-like receptor 3 (NLRP-3) in renal tissues were examined. Activation of caspase-1 and the maturation of pro- IL-1β and pro- IL-18 were also examined.
Results: Albuminuria and tubulointerstitial damage were developed in the Ald group. Increased expressions of NLRP-3, ASC, and caspase-1 in renal tissues were detected in the Ald group. Proteolytic processing and secretion of IL-1βand IL-18 were augmented in Ald-treated renal tissues. These changes were suppressed in the Ald+Spi group in a blood pressure independent manner. Furthermore, immunohistochemical analysis, using monoclonal antibodies for inflammasome components, revealed that inflammasomes were activated in the macrophages infiltrating in the interstitium.
Conclusions: Aldosterone induces activation of inflammasomes in macrophages and evokes inflammatory responses in renal interstitium. Activation of inflammasome could serve as potential therapeutic target for chronic kidney diseases.
- © 2012 by American Heart Association, Inc.