The inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induce hypertension in mice

Krishnan, S. M., Dowling, J. K., Ling, Y. H., Diep, H., Chan, C. T., Ferens, D., Kett, M. M., Pinar, A., Samuel, C. S., Vinh, A., Arumugam, T. V., Hewitson, T. D., Kemp-Harper, B. K., Robertson, A. A. B., Cooper, M. A., Latz, E., Mansell, A., Sobey, C. G. and Drummond, G. R. (2015) The inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induce hypertension in mice. British Journal of Pharmacology, 173 4: 752-765. doi:10.1111/bph.13230

Author Krishnan, S. M.
Dowling, J. K.
Ling, Y. H.
Diep, H.
Chan, C. T.
Ferens, D.
Kett, M. M.
Pinar, A.
Samuel, C. S.
Vinh, A.
Arumugam, T. V.
Hewitson, T. D.
Kemp-Harper, B. K.
Robertson, A. A. B.
Cooper, M. A.
Latz, E.
Mansell, A.
Sobey, C. G.
Drummond, G. R.
Title The inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induce hypertension in mice
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
Publication date 2015-07-31
Sub-type Article (original research)
DOI 10.1111/bph.13230
Open Access Status Not yet assessed
Volume 173
Issue 4
Start page 752
End page 765
Total pages 14
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Collection year 2016
Language eng
Formatted 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.
Keyword Inflammasomes
Clinical hypertension
Renal Expression
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Early view of article. Published online 31 July 2015.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Created: Wed, 22 Jul 2015, 10:35:30 EST by Susan Allen on behalf of Institute for Molecular Bioscience