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.
PY - 2021/11/1
Y1 - 2021/11/1
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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UR - http://www.scopus.com/inward/citedby.url?scp=85117398521&partnerID=8YFLogxK
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 -