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Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension

AIMS: Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated wh...

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Autores principales: Krishnan, Shalini M, Ling, Yeong H, Huuskes, Brooke M, Ferens, Dorota M, Saini, Narbada, Chan, Christopher T, Diep, Henry, Kett, Michelle M, Samuel, Chrishan S, Kemp-Harper, Barbara K, Robertson, Avril A B, Cooper, Matthew A, Peter, Karlheinz, Latz, Eicke, Mansell, Ashley S, Sobey, Christopher G, Drummond, Grant R, Vinh, Antony
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432065/
https://www.ncbi.nlm.nih.gov/pubmed/30357309
http://dx.doi.org/10.1093/cvr/cvy252
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author Krishnan, Shalini M
Ling, Yeong H
Huuskes, Brooke M
Ferens, Dorota M
Saini, Narbada
Chan, Christopher T
Diep, Henry
Kett, Michelle M
Samuel, Chrishan S
Kemp-Harper, Barbara K
Robertson, Avril A B
Cooper, Matthew A
Peter, Karlheinz
Latz, Eicke
Mansell, Ashley S
Sobey, Christopher G
Drummond, Grant R
Vinh, Antony
author_facet Krishnan, Shalini M
Ling, Yeong H
Huuskes, Brooke M
Ferens, Dorota M
Saini, Narbada
Chan, Christopher T
Diep, Henry
Kett, Michelle M
Samuel, Chrishan S
Kemp-Harper, Barbara K
Robertson, Avril A B
Cooper, Matthew A
Peter, Karlheinz
Latz, Eicke
Mansell, Ashley S
Sobey, Christopher G
Drummond, Grant R
Vinh, Antony
author_sort Krishnan, Shalini M
collection PubMed
description AIMS: Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension. METHODS AND RESULTS: C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25–40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206(+) (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na(+)], and albuminuria (each by 20–25%). None of the above parameters were altered by MCC950 in normotensive mice. CONCLUSION: MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy.
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spelling pubmed-64320652019-04-01 Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension Krishnan, Shalini M Ling, Yeong H Huuskes, Brooke M Ferens, Dorota M Saini, Narbada Chan, Christopher T Diep, Henry Kett, Michelle M Samuel, Chrishan S Kemp-Harper, Barbara K Robertson, Avril A B Cooper, Matthew A Peter, Karlheinz Latz, Eicke Mansell, Ashley S Sobey, Christopher G Drummond, Grant R Vinh, Antony Cardiovasc Res Original Articles AIMS: Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension. METHODS AND RESULTS: C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25–40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206(+) (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na(+)], and albuminuria (each by 20–25%). None of the above parameters were altered by MCC950 in normotensive mice. CONCLUSION: MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy. Oxford University Press 2019-04-01 2018-10-24 /pmc/articles/PMC6432065/ /pubmed/30357309 http://dx.doi.org/10.1093/cvr/cvy252 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Krishnan, Shalini M
Ling, Yeong H
Huuskes, Brooke M
Ferens, Dorota M
Saini, Narbada
Chan, Christopher T
Diep, Henry
Kett, Michelle M
Samuel, Chrishan S
Kemp-Harper, Barbara K
Robertson, Avril A B
Cooper, Matthew A
Peter, Karlheinz
Latz, Eicke
Mansell, Ashley S
Sobey, Christopher G
Drummond, Grant R
Vinh, Antony
Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension
title Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension
title_full Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension
title_fullStr Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension
title_full_unstemmed Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension
title_short Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension
title_sort pharmacological inhibition of the nlrp3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432065/
https://www.ncbi.nlm.nih.gov/pubmed/30357309
http://dx.doi.org/10.1093/cvr/cvy252
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