Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension. (February 2017)

• Record Type: Journal Article
• Authors: Ling, Yeong Hann; Krishnan, Shalini M.; Chan, Christopher T.; Diep, Henry; Ferens, Dorota; Chin-Dusting, Jaye; Kemp-Harper, Barbara K.; Samuel, Chrishan S.; Hewitson, Timothy D.; Latz, Eicke; Mansell, Ashley; Sobey, Christopher G.; Drummond, Grant R.
• Is Part Of: Pharmacological research. Volume 116(2017:Feb.)
• Page Start: 77
• Page End: 86
• Publication Date: 2017-02
• Subjects: ASC apoptosis-associated speck-like protein containing a (CARD) -- BP blood pressure -- CARD caspase activation and recruitment domain -- CCL2 chemokine ligand 2 -- CCL5 chemokine ligand 5 -- cDNA complementary DNA -- DAMP danger-associated molecular pattern -- DOCA deoxycorticosterone acetate -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- HRP horseradish peroxidase -- HSP heat shock protein -- ICAM-1 intercellular adhesion molecule 1 -- IL-18 interleukin 18 -- IL-18R interleukin 18 receptor -- IL-18RAcP interleukin 18 receptor accessory protein -- IL-1R interleukin 1 receptor -- IL-1RA interleukin 1 receptor antagonist -- IL-1β interleukin 1β -- IL-6 interleukin 6 -- mmHg millimetres of mercury -- MW molecular weight -- NF-κB nuclearfactor kappa-light-chain-enhancer of activated B cells -- NLR nod-like receptor -- NLRC nod-like receptor with caspase-recruitment domain -- NLRP nod-like receptor with pyrin domain -- NLRP3 nod-like receptor with pyrin domain containing 3 -- PAMP pathogen-associated molecular pattern -- PBS phosphate-buffered saline -- PCR polymerase chain reaction -- PRR pattern recognition receptor -- RNA ribonucleic acid -- SPF specific pathogen free -- TLR toll-like receptor -- VCAM-1 vascular cell adhesion molecule 1; High blood pressure -- Inflammasomes -- IL-1β -- Inflammation -- Kidney -- Anakinra; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.12.015
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Objective: To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. Methods: Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c. ) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10 days post-surgery, mice commenced treatment with anakinra (75 mg/kg/d, i.p. ) or vehicle (0.9% saline, i.p. ) for 11 days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. Results: By 10 days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3 ± 2.4 mmHg) compared to control mice (121.7 ± 2.7 mmHg; n = 18, P < 0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by ∼20 mmHg (n = 16, P < 0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced (∼30%) renal expression of some (CCL5, CCL2; n = 7–8; P < 0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n = 7–8, P > 0.05). Anakinra reduced renal collagen content (n = 6, P < 0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n = 8-9, P < 0.001) that accompanied 1K/DOCA/salt-induced hypertension. Conclusion: Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain.