Abstract 254: Inflammasome Activity Is Essential For Deoxycorticosterone Acetate/salt-induced Hypertension In Mice

Inflammasomes are signalling complexes comprised of a NOD-like receptor protein (NLRP), an adapter protein (ASC) and caspase-1. Inflammasomes detect host-derived danger signals and induce inflammation via activation of caspase-1, which in turn cleaves the cytokines pro-interleukin(IL)-1β and pro-IL-18 into their active, pro-inflammatory forms. Hypertension is associated with chronic renal inflammation, but the role of the inflammasome in this process is not known. Hence, we tested whether deoxycorticosterone acetate (DOCA)/salt-induced hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and assessed the impact of inhibition of inflammasome activity on blood pressure (BP) and markers of renal inflammation and fibrosis. Male C57BL6/J (wild type) and ASC -/- mice were uninephrectomised, implanted with a DOCA pellet (2.4 mg/d, 21 d, s.c. ) and had their drinking water replaced with 1% saline (1K/DOCA/salt). Control mice had a kidney removed but received a placebo pellet and normal drinking water. 1K/DOCA/salt-treated mice had elevated systolic BP (146±4 mmHg) compared to control mice (115±2 mmHg; n=13-16; P -/- mice, which lack an active inflammasome complex, displayed blunted hypertensive responses to 1K/DOCA/salt-treatment (140±3 mmHg) compared to wild types (155±8 mmHg; n=8-9; P -/- mice were also protected from 1K/DOCA/salt-induced increases in renal expression of the inflammatory genes IL-6, IL-17a, CCL2, ICAM-1 and VCAM-1, and accumulation of collagen. Thus, renal inflammation, fibrosis and elevated BP in response to 1K/DOCA/salt-treatment are critically dependent on inflammasome activity, highlighting this signalling complex and its cytokine products as potential therapeutic targets to treat hypertension.