Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension

Yeong Hann Ling, Shalini M. Krishnan, Christopher T. Chan, Henry Diep, Dorota Ferens, Jaye Chin-Dusting, Barbara K. Kemp-Harper, Chrishan S. Samuel, Timothy D. Hewitson, Eicke Latz, Ashley Mansell, Christopher G. Sobey, Grant R. Drummond

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)77-86
Number of pages10
JournalPharmacological Research
Volume116
DOIs
Publication statusPublished - Feb 2017

Keywords

  • Anakinra
  • High blood pressure
  • IL-1β
  • Inflammasomes
  • Inflammation
  • Kidney

Cite this

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. / Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension. In: Pharmacological Research. 2017 ; Vol. 116. pp. 77-86.
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title = "Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension",
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.",
keywords = "Anakinra, High blood pressure, IL-1β, Inflammasomes, Inflammation, Kidney",
author = "Ling, {Yeong Hann} and Krishnan, {Shalini M.} and Chan, {Christopher T.} and Henry Diep and Dorota Ferens and Jaye Chin-Dusting and Kemp-Harper, {Barbara K.} and Samuel, {Chrishan S.} and Hewitson, {Timothy D.} and Eicke Latz and Ashley Mansell and Sobey, {Christopher G.} and Drummond, {Grant R.}",
year = "2017",
month = "2",
doi = "10.1016/j.phrs.2016.12.015",
language = "English",
volume = "116",
pages = "77--86",
journal = "Pharmacological Research",
issn = "1043-6618",
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Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension. / 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.

In: Pharmacological Research, Vol. 116, 02.2017, p. 77-86.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension

AU - Ling, Yeong Hann

AU - Krishnan, Shalini M.

AU - Chan, Christopher T.

AU - Diep, Henry

AU - Ferens, Dorota

AU - Chin-Dusting, Jaye

AU - Kemp-Harper, Barbara K.

AU - Samuel, Chrishan S.

AU - Hewitson, Timothy D.

AU - Latz, Eicke

AU - Mansell, Ashley

AU - Sobey, Christopher G.

AU - Drummond, Grant R.

PY - 2017/2

Y1 - 2017/2

N2 - 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.

AB - 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.

KW - Anakinra

KW - High blood pressure

KW - IL-1β

KW - Inflammasomes

KW - Inflammation

KW - Kidney

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U2 - 10.1016/j.phrs.2016.12.015

DO - 10.1016/j.phrs.2016.12.015

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EP - 86

JO - Pharmacological Research

JF - Pharmacological Research

SN - 1043-6618

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