MPS 13-08 EXCESS ALDOSTERONE IS A CRITICAL DANGER SIGNAL FOR INFLAMMASOME ACTIVATION IN THE DEVELOPMENT OF RENAL FIBROSIS IN MICE

Abstract

High levels of aldosterone impair renal function by activating proinflammatory and profibrotic pathways. However, the molecular mechanism underlying aldosterone-induced inflammation and fibrosis is unknown. Inflammasome activation contributes to chronic kidney disease. We hypothesized that aldosterone induces renal tubulointerstitial inflammation and fibrosis by activating the inflammasome.

We used ASC-deficient mice (ASCKO) to investigate the role of inflammasome, which ASC is a critical component of the inflammasomes. C57Bl/6 mice (WT) were used for control. All animals were received left uninephrectomy and given drinking water with 1% NaCl. The mice were divided into the following groups: WT-vehicle (WT-vehi), WT-Aldo (WT-Aldo; 0.25 mg/kg/day, osmotic pump), WT-Aldo treated with eplerenone (WT-Aldo + Eple; 100 mg/kg/day, gavage), ASCKO-vehicle (ASCKO-vehi), ASCKO-Aldo (ASCKO-Aldo). Three weeks after drug administration, mice were sacrificed. In vitro assay, we investigated the mitochondrial superoxide production by Aldo, which is a trigger of inflammasome activation.

Infusing wild-type mice with aldosterone caused tubulointerstitial damage, increased expression of inflammasome components, caspase-1 activation, and overproduction of interleukin-1β and interleukin-18. These changes were suppressed by eplerenone treatment in wild-type mice or in mice deficient in apoptosis-associated speck-like protein with a caspase-recruitment domain. Caspase-1-positive and F4/80-positive cells colocalized in the interstitium. Bone marrow transplantation using ASC-deficient mice indicated that inflammasome activation in macrophages mediated aldosterone-induced renal fibrosis. Interleukin-18 was detected in culture supernatants of macrophages treated with aldosterone, and mitochondria-derived reactive oxygen species activated the inflammasome in these macrophages.

Our results indicate that exposure of macrophages to high levels of aldosterone resulted in the activation of inflammasomes via the mitochondria-derived reactive oxygen species. Thus, inflammasome activation in macrophages may serve as a new therapeutic target for chronic kidney disease.