title: Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Krishnan
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Clayton, Vic., Australia.
authors.forename: J K
authors.initials: JK
authors.lastname: Dowling
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.
authors.forename: Y H
authors.initials: YH
authors.lastname: Ling
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.
authors.forename: H
authors.initials: H
authors.lastname: Diep
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.
authors.forename: C T
authors.initials: CT
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.
authors.forename: D
authors.initials: D
authors.lastname: Ferens
authors.affiliation: Department of Physiology, Monash University, Clayton, Vic., Australia.
authors.forename: M M
authors.initials: MM
authors.lastname: Kett
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Clayton, Vic., Australia.
authors.forename: A
authors.initials: A
authors.lastname: Pinar
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.
authors.forename: C S
authors.initials: CS
authors.lastname: Samuel
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.
authors.forename: A
authors.initials: A
authors.lastname: Vinh
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: T V
authors.initials: TV
authors.lastname: Arumugam
authors.affiliation: Department of Nephrology, Royal Melbourne Hospital, Parkville, Vic., Australia.
authors.forename: T D
authors.initials: TD
authors.lastname: Hewitson
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.
authors.forename: B K
authors.initials: BK
authors.lastname: Kemp-Harper
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: A A B
authors.initials: AA
authors.lastname: Robertson
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.|Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.|German Center for Neurodegenerative Diseases, Bonn, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Latz
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Clayton, Vic., Australia.
authors.forename: A
authors.initials: A
authors.lastname: Mansell
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.|Department of Surgery, Monash Medical Centre, Southern Clinical School, Monash University, Clayton, Vic., Australia.
authors.forename: C G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Vic., Australia.|Department of Surgery, Monash Medical Centre, Southern Clinical School, Monash University, Clayton, Vic., Australia.
authors.forename: G R
authors.initials: GR
authors.lastname: Drummond
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D003900:Desoxycorticosterone / Q000008:administration & dosage; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012492:Salts / Q000008:administration & dosage
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D058847:Inflammasomes; C498534:Pycard protein, mouse; D012492:Salts; D003900:Desoxycorticosterone