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<0.05). 1K/DOCA/salt-induced hypertension was associated with increased renal mRNA expression (fold-change vs control; n=7-9; P<0.05) of inflammasome subunits NLRP3 (2.3±0.2), ASC (2.8±0.6) and pro-caspase-1 (2.6±0.5), and the cytokine, pro-IL-1 (4.0±0.8). Moreover, protein levels of cleaved (active) caspase-1 and IL-1 were increased by 1.6±0.2- and 2.1±0.3-fold, respectively in kidneys of 1K/DOCA/salt vs control mice (n=6; P<0.05). ASC-/- 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<0.05). ASC-/- 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.
Author Disclosures: S.M. Krishnan: None. C.G. Sobey: None. B. Kemp-Harper: None. C.T. Chan: None. H. Diep: None. J. Dowling: None. A. Pinar: None. A. Mansell: None. G.R. Drummond: None.
- © 2014 by American Heart Association, Inc.