PMID- 34488433
OWN - NLM
STAT- MEDLINE
DCOM- 20220119
LR  - 20240226
IS  - 1524-4563 (Electronic)
IS  - 0194-911X (Linking)
VI  - 78
IP  - 5
DP  - 2021 Nov
TI  - IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal 
      Inflammation and Injury During Deoxycorticosterone/Salt-Induced Hypertension in 
      Mice.
PG  - 1296-1309
LID - 10.1161/HYPERTENSIONAHA.120.16437 [doi]
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-gamma 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.
FAU - Thomas, Jordyn M
AU  - Thomas JM
AUID- ORCID: 0000-0001-7544-4077
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
FAU - Ling, Yeong H
AU  - Ling YH
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Cardiovascular 
      Disease Program, Monash University, Clayton, Australia (Y.H.L., D.M.F., S.M.K., 
      B.K.K.-H.).
FAU - Huuskes, Brooke
AU  - Huuskes B
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
FAU - Jelinic, Maria
AU  - Jelinic M
AUID- ORCID: 0000-0001-9773-4972
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
FAU - Sharma, Prerna
AU  - Sharma P
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
FAU - Saini, Narbada
AU  - Saini N
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
FAU - Ferens, Dorota M
AU  - Ferens DM
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Cardiovascular 
      Disease Program, Monash University, Clayton, Australia (Y.H.L., D.M.F., S.M.K., 
      B.K.K.-H.).
FAU - Diep, Henry
AU  - Diep H
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
FAU - Krishnan, Shalini M
AU  - Krishnan SM
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Cardiovascular 
      Disease Program, Monash University, Clayton, Australia (Y.H.L., D.M.F., S.M.K., 
      B.K.K.-H.).
FAU - Kemp-Harper, Barbara K
AU  - Kemp-Harper BK
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Cardiovascular 
      Disease Program, Monash University, Clayton, Australia (Y.H.L., D.M.F., S.M.K., 
      B.K.K.-H.).
FAU - O'Connor, Paul M
AU  - O'Connor PM
AD  - Department of Physiology, Medical College of Georgia, Augusta University 
      (P.M.O.).
FAU - Latz, Eicke
AU  - Latz E
AD  - Institute of Innate Immunity, University Hospital, University of Bonn, Germany 
      (E.L.).
AD  - German Center for Neurodegenerative Diseases, Bonn, Germany (E.L.).
FAU - Arumugam, Thiruma V
AU  - Arumugam TV
AUID- ORCID: 0000-0002-3377-0939
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
FAU - Guzik, Tomasz J
AU  - Guzik TJ
AD  - Department of Medicine, Jagiellonian University, Collegium Medicum, Krakow, 
      Poland (T.J.G.).
AD  - BHF Centre of Research Excellence, Institute of Cardiovascular and Medical 
      Sciences, University of Glasgow, United Kingdom (T.J.G.).
FAU - Hickey, Michael J
AU  - Hickey MJ
AD  - Department of Medicine, Centre for Inflammatory Diseases, Monash University, 
      Clayton, Australia (M.J.H.).
FAU - Mansell, Ashley
AU  - Mansell A
AD  - Hudson Institute of Medical Research, Clayton, Australia (A.M.).
FAU - Sobey, Christopher G
AU  - Sobey CG
AUID- ORCID: 0000-0001-6525-9097
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
AD  - Baker Heart and Diabetes Institute, Prahran, Australia (C.G.S., G.R.D.).
FAU - Vinh, Antony
AU  - Vinh A
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
FAU - Drummond, Grant R
AU  - Drummond GR
AD  - Centre for Cardiovascular Biology and Disease Research and Department of 
      Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe 
      University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., 
      C.G.S., A.V., G.R.D.).
AD  - Baker Heart and Diabetes Institute, Prahran, Australia (C.G.S., G.R.D.).
LA  - eng
GR  - R21 AI150723/AI/NIAID NIH HHS/United States
GR  - P01 HL134604/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210907
PL  - United States
TA  - Hypertension
JT  - Hypertension (Dallas, Tex. : 1979)
JID - 7906255
RN  - 0 (Interleukin-18)
RN  - 6E0A168OB8 (Desoxycorticosterone Acetate)
SB  - IM
MH  - Albuminuria/chemically induced/genetics/metabolism
MH  - Animals
MH  - Blood Pressure/genetics/physiology
MH  - Desoxycorticosterone Acetate
MH  - Epithelial Cells/*metabolism
MH  - Hypertension/chemically induced/genetics/*physiopathology
MH  - Inflammation/genetics/*metabolism
MH  - Interleukin-18/genetics/*metabolism
MH  - Kidney/metabolism/pathology
MH  - Kidney Diseases/genetics/*metabolism
MH  - Kidney Tubules/cytology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - T-Lymphocytes/immunology/metabolism
MH  - Mice
OTO - NOTNLM
OT  - blood pressure
OT  - fibrosis
OT  - hypertension
OT  - inflammation
OT  - interleukin-18
EDAT- 2021/09/08 06:00
MHDA- 2022/01/20 06:00
CRDT- 2021/09/07 05:44
PHST- 2021/09/08 06:00 [pubmed]
PHST- 2022/01/20 06:00 [medline]
PHST- 2021/09/07 05:44 [entrez]
AID - 10.1161/HYPERTENSIONAHA.120.16437 [doi]
PST - ppublish
SO  - Hypertension. 2021 Nov;78(5):1296-1309. doi: 10.1161/HYPERTENSIONAHA.120.16437. 
      Epub 2021 Sep 7.