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

Shalini M. Krishnan, Yeong H. Ling, Brooke M. Huuskes, Dorota M. Ferens, Narbada Saini, Christopher T. Chan, Henry Diep, Michelle M. Kett, Chrishan S. Samuel, Barbara K. Kemp-Harper, Avril A.B. Robertson, Matthew A. Cooper, Karlheinz Peter, Eicke Latz, Ashley S. Mansell, Christopher G. Sobey, Grant R. Drummond, Antony Vinh

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)776-787
Number of pages12
JournalCardiovascular Research
Volume115
Issue number4
DOIs
Publication statusPublished - 15 Mar 2019

Keywords

  • Hypertension
  • MCC950
  • NLRP3 inflammasome
  • Renal fibrosis
  • Renal inflammation

Cite this

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. In: Cardiovascular Research. 2019 ; Vol. 115, No. 4. pp. 776-787.
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abstract = "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.",
keywords = "Hypertension, MCC950, NLRP3 inflammasome, Renal fibrosis, Renal inflammation",
author = "Krishnan, {Shalini M.} and Ling, {Yeong H.} and Huuskes, {Brooke M.} and Ferens, {Dorota M.} and Narbada Saini and Chan, {Christopher T.} and Henry Diep and Kett, {Michelle M.} and Samuel, {Chrishan S.} and Kemp-Harper, {Barbara K.} and Robertson, {Avril A.B.} and Cooper, {Matthew A.} and Karlheinz Peter and Eicke Latz and Mansell, {Ashley S.} and Sobey, {Christopher G.} and Drummond, {Grant R.} and Antony Vinh",
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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.

In: Cardiovascular Research, Vol. 115, No. 4, 15.03.2019, p. 776-787.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension

AU - Krishnan, Shalini M.

AU - Ling, Yeong H.

AU - Huuskes, Brooke M.

AU - Ferens, Dorota M.

AU - Saini, Narbada

AU - Chan, Christopher T.

AU - Diep, Henry

AU - Kett, Michelle M.

AU - Samuel, Chrishan S.

AU - Kemp-Harper, Barbara K.

AU - Robertson, Avril A.B.

AU - Cooper, Matthew A.

AU - Peter, Karlheinz

AU - Latz, Eicke

AU - Mansell, Ashley S.

AU - Sobey, Christopher G.

AU - Drummond, Grant R.

AU - Vinh, Antony

PY - 2019/3/15

Y1 - 2019/3/15

N2 - 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.

AB - 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.

KW - Hypertension

KW - MCC950

KW - NLRP3 inflammasome

KW - Renal fibrosis

KW - Renal inflammation

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U2 - 10.1093/cvr/cvy252

DO - 10.1093/cvr/cvy252

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VL - 115

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EP - 787

JO - Cardiovascular Research

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SN - 0008-6363

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