IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury during Deoxycorticosterone/Salt-Induced Hypertension in Mice

Jordyn M. Thomas; Yeong H. Ling; Brooke Huuskes; Maria Jelinic; Prerna Sharma; Narbada Saini; Dorota M. Ferens; Henry Diep; Shalini M. Krishnan; Barbara K. Kemp-Harper; Paul M. O'Connor; Eicke Latz; Thiruma V. Arumugam; Tomasz J. Guzik; Michael J. Hickey; Ashley Mansell; Christopher G. Sobey; Antony Vinh; Grant R. Drummond

doi:10.1161/HYPERTENSIONAHA.120.16437

IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury during Deoxycorticosterone/Salt-Induced Hypertension in Mice

Jordyn M. Thomas, Yeong H. Ling, Brooke Huuskes, Maria Jelinic, Prerna Sharma, Narbada Saini, Dorota M. Ferens, Henry Diep, Shalini M. Krishnan, Barbara K. Kemp-Harper, Paul M. O'Connor, Eicke Latz, Thiruma V. Arumugam, Tomasz J. Guzik, Michael J. Hickey, Ashley Mansell, Christopher G. Sobey, Antony Vinh, Grant R. Drummond

Research output: Contribution to journal › Article › Research › peer-review

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Abstract

IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18^-/-mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3⁺T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18^-/-mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18^-/-mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits - interleukin-18 receptor 1 and IL-18R accessory protein - were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.

Original language	English
Pages (from-to)	1296-1309
Number of pages	14
Journal	Hypertension
Volume	78
Issue number	5
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.120.16437
Publication status	Published - Nov 2021

Keywords

blood pressure
fibrosis
hypertension
inflammation
interleukin-18

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10.1161/HYPERTENSIONAHA.120.16437

Cite this

Thomas, J. M., Ling, Y. H., Huuskes, B., Jelinic, M., Sharma, P., Saini, N., Ferens, D. M., Diep, H., Krishnan, S. M., Kemp-Harper, B. K., O'Connor, P. M., Latz, E., Arumugam, T. V., Guzik, T. J., Hickey, M. J., Mansell, A., Sobey, C. G., Vinh, A., & Drummond, G. R. (2021). IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury during Deoxycorticosterone/Salt-Induced Hypertension in Mice. Hypertension, 78(5), 1296-1309. https://doi.org/10.1161/HYPERTENSIONAHA.120.16437

@article{469d91aef2a54a7c815723592fda9acf,

title = "IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury during Deoxycorticosterone/Salt-Induced Hypertension in Mice",

abstract = "IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18-/-mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3+T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18-/-mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18-/-mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits - interleukin-18 receptor 1 and IL-18R accessory protein - were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.",

keywords = "blood pressure, fibrosis, hypertension, inflammation, interleukin-18",

author = "Thomas, {Jordyn M.} and Ling, {Yeong H.} and Brooke Huuskes and Maria Jelinic and Prerna Sharma and Narbada Saini and Ferens, {Dorota M.} and Henry Diep and Krishnan, {Shalini M.} and Kemp-Harper, {Barbara K.} and O'Connor, {Paul M.} and Eicke Latz and Arumugam, {Thiruma V.} and Guzik, {Tomasz J.} and Hickey, {Michael J.} and Ashley Mansell and Sobey, {Christopher G.} and Antony Vinh and Drummond, {Grant R.}",

note = "Funding Information: This work was supported by the National Health and Medical Research Council of Australia (GNT1143674 to G.R. Drummond, M.J. Hickey, A. Mansell, C.G. Sobey, and A. Vinh; GNT1079467 to C.G. Sobey; GNT1042775 to M.J. Hickey), the European Research Council (InflammaTENSION 726318 to T.J. Guzik), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany{\textquoteright}s Excellence Strategy (EXC2151—390873048 to E. Latz) and the National Institutes of Health (1P01HL134604-01 and R21AI150723 to P.M. O{\textquoteright}Connor). Publisher Copyright: {\textcopyright} 2021 Lippincott Williams and Wilkins. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = nov,

doi = "10.1161/HYPERTENSIONAHA.120.16437",

language = "English",

volume = "78",

pages = "1296--1309",

journal = "Hypertension",

issn = "0194-911X",

publisher = "American Heart Association",

number = "5",

}

Thomas, JM, Ling, YH, Huuskes, B, Jelinic, M, Sharma, P, Saini, N, Ferens, DM, Diep, H, Krishnan, SM, Kemp-Harper, BK, O'Connor, PM, Latz, E, Arumugam, TV, Guzik, TJ, Hickey, MJ , Mansell, A , Sobey, CG , Vinh, A & Drummond, GR 2021, 'IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury during Deoxycorticosterone/Salt-Induced Hypertension in Mice', Hypertension, vol. 78, no. 5, pp. 1296-1309. https://doi.org/10.1161/HYPERTENSIONAHA.120.16437

TY - JOUR

T1 - IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury during Deoxycorticosterone/Salt-Induced Hypertension in Mice

AU - Thomas, Jordyn M.

AU - Ling, Yeong H.

AU - Huuskes, Brooke

AU - Jelinic, Maria

AU - Sharma, Prerna

AU - Saini, Narbada

AU - Ferens, Dorota M.

AU - Diep, Henry

AU - Krishnan, Shalini M.

AU - Kemp-Harper, Barbara K.

AU - O'Connor, Paul M.

AU - Latz, Eicke

AU - Arumugam, Thiruma V.

AU - Guzik, Tomasz J.

AU - Hickey, Michael J.

AU - Mansell, Ashley

AU - Sobey, Christopher G.

AU - Vinh, Antony

AU - Drummond, Grant R.

N1 - Funding Information: This work was supported by the National Health and Medical Research Council of Australia (GNT1143674 to G.R. Drummond, M.J. Hickey, A. Mansell, C.G. Sobey, and A. Vinh; GNT1079467 to C.G. Sobey; GNT1042775 to M.J. Hickey), the European Research Council (InflammaTENSION 726318 to T.J. Guzik), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy (EXC2151—390873048 to E. Latz) and the National Institutes of Health (1P01HL134604-01 and R21AI150723 to P.M. O’Connor). Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/11

Y1 - 2021/11

N2 - IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18-/-mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3+T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18-/-mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18-/-mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits - interleukin-18 receptor 1 and IL-18R accessory protein - were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.

AB - IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18-/-mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3+T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18-/-mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18-/-mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits - interleukin-18 receptor 1 and IL-18R accessory protein - were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.

KW - blood pressure

KW - fibrosis

KW - hypertension

KW - inflammation

KW - interleukin-18

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U2 - 10.1161/HYPERTENSIONAHA.120.16437

DO - 10.1161/HYPERTENSIONAHA.120.16437

M3 - Article

C2 - 34488433

AN - SCOPUS:85117398521

SN - 0194-911X

VL - 78

SP - 1296

EP - 1309

JO - Hypertension

JF - Hypertension

IS - 5

ER -

IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury during Deoxycorticosterone/Salt-Induced Hypertension in Mice

Abstract

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INFLAMMASOMES AND INTERLEUKIN-18 SIGNALLING: NOVEL BIOMARKERS AND THERAPEUTIC TARGETS FOR KIDNEY DISEASE

NHMRC Research Fellowship

NHMRC Research Fellowship

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IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury during Deoxycorticosterone/Salt-Induced Hypertension in Mice

Abstract

Keywords

Access to Document

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INFLAMMASOMES AND INTERLEUKIN-18 SIGNALLING: NOVEL BIOMARKERS AND THERAPEUTIC TARGETS FOR KIDNEY DISEASE

NHMRC Research Fellowship

NHMRC Research Fellowship

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