Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice
In: British Journal of Pharmacology, Jg. 173 (2015-07-31), S. 752-765
Online
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Zugriff:
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. Linked Articles This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4
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Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice
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Autor/in / Beteiligte Person: | Sobey, Christopher G. ; Hewitson, Tim D. ; Grant R Drummond ; Yeong Hann Ling ; Latz, Eicke ; Cooper, Mark E. ; Shalini M Krishnan ; Michelle M Kett ; Ferens, Dorota ; Barbara K Kemp-Harper ; Pinar, Anita A. ; Diep, Henry ; Mansell, Ashley ; Chan, Christopher T. ; Samuel, Chrishan S. ; Dowling, Jennifer K. ; Vinh, Antony ; Robertson, Avril A. B. ; Arumugam, Thiruma V. |
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Zeitschrift: | British Journal of Pharmacology, Jg. 173 (2015-07-31), S. 752-765 |
Veröffentlichung: | Wiley, 2015 |
Medientyp: | unknown |
ISSN: | 0007-1188 (print) |
DOI: | 10.1111/bph.13230 |
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