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Interleukin‐18 is Crucial for the Development of Renal Inflammation and Elevated Blood Pressure in a Mouse Model of Hypertension
Author(s) -
Ling Yeong Hann,
Thomas Jordyn,
Krishnan Shalini Murali,
Ferens Dorota,
Masters Seth,
KempHarper Barbara,
Mansell Ashley,
Sobey Christopher,
Drummond Grant
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.998.1
Subject(s) - inflammation , medicine , endocrinology , blood pressure , kidney , immune system , ccl2 , interleukin 18 , cytokine , inflammasome , chemokine , immunology
Background Interleukin‐18 (IL‐18) is a cytokine released downstream of inflammasome activation that promotes pro‐inflammatory T H 1 immune responses. Clinical studies have shown that levels of IL‐18 are elevated in hypertensive patients. However, whether IL‐18 plays a causal role in hypertension is unknown. Aims To determine if IL‐18 and/or its receptor (IL‐18R) are upregulated in kidneys of hypertensive mice and to establish if IL‐18 deficiency protects mice against the development of hypertension and renal inflammation. Methods Hypertension was induced in male wild‐type and IL‐18 −/− mice by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/d, s.c. ) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water (1K/placebo). Systolic blood pressure (BP) was measured by tail cuff. After 21 days, kidneys were harvested to assess: renal hypertrophy; expression of IL‐18, IL‐18R, and the inflammatory markers ICAM‐1, VCAM‐1, CCL5 and CCL2 by real‐time PCR; and immune cell numbers and cellular expression of IL‐18R by flow cytometry. Results 1K/DOCA/salt‐treated mice displayed elevated BP and kidney weights (140±3 mmHg; 390±8 mg) compared to 1K/placebo mice (118±2 mmHg; 291±7 mg; n≥17, P<0.05). 1K/DOCA/salt treatment also caused renal inflammation as indicated by ≥2‐fold increases in CD45+ leukocyte numbers, and expression of ICAM‐1, VCAM‐1, CCL5 and CCL2 (n≥7, P<0.001). IL‐18 expression was ~2‐fold higher in the kidneys of 1K/DOCA/salt versus 1K/placebo mice (n≥7; P<0.01). IL‐18R expression was also elevated by 3‐fold (n≥6; P<0.0001) with infiltrating CD4+ T cells representing the major cell type expressing this receptor. Importantly, IL‐18 −/− mice were profoundly protected from the hypertensive actions of 1K/DOCA/salt compared to wild‐type mice (119±6 vs 145±6 mmHg; n=5, P<0.05) and displayed marked reductions (i.e. >2‐fold) in renal expression levels of ICAM‐1, VCAM‐1 and CCL2 (n≥4, P<0.05). Conclusion Upregulation of IL‐18 and its receptor is a major driver of renal inflammation and the development of hypertension following 1K/DOCA/salt‐treatment in mice. Hence, these findings highlight the IL‐18 signalling system as a potential target for future anti‐hypertensive therapies. Support or Funding Information NHMRC Project Grant APP1041326