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Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice.

Abstract：

BACKGROUND AND PURPOSE:Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines IL-1β and IL-18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL-1β and IL-18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis. EXPERIMENTAL APPROACH:Wild-type and inflammasome-deficient ASC(-/-) mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real-time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry. KEY RESULTS:1K/DOCA/salt-induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro-caspase-1, and the cytokine, pro-IL-1β, as well as protein levels of active caspase-1 and mature IL-1β. Following treatment with 1K/DOCA/salt, ASC(-/-) mice displayed blunted pressor responses and were also protected from increases in renal expression of IL-6, IL-17A, CCL2, ICAM-1 and VCAM-1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt-treated mice. CONCLUSIONS AND IMPLICATIONS:Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL-1β pathway as a potential therapeutic target in hypertension.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Krishnan SM,Dowling JK,Ling YH,Diep H,Chan CT,Ferens D,Kett MM,Pinar A,Samuel CS,Vinh A,Arumugam TV,Hewitson TD,Kemp-Harper BK,Robertson AA,Cooper MA,Latz E,Mansell A,Sobey CG,Drummond GR

doi

10.1111/bph.13230

subject

Has Abstract

pub_date

2016-02-01 00:00:00

pages

752-65

issue

eissn

0007-1188

issn

1476-5381

journal_volume

173

pub_type

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Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice.