J THOMAS1, Y LING1, S KRISHNAN2, D FERENS2, B KEMP-HARPER2, C SOBEY1, G DRUMMOND1, B HUUSKES1, A VINH1
1Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Australia, 2Department of Pharmacology, Monash University, Clayton, Australia
Aim: To test the hypothesis that Interleukin-18 (IL-18) signalling contributes to the development of experimental hypertension and renal inflammation.
Background: 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.
Methods: Hypertension was induced in male wild-type (WT) and IL-18-/- mice by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/d, s.c.) and saline (0.9%) drinking water (1K/DOCA/salt). Blood pressure (BP) was measured via tail cuff and radiotelemetry, and after 21 days kidneys were harvested for histopathological, mRNA and flow cytometric analyses.
Results: 1K/DOCA/salt-treated mice had higher BPs (140±3mmHg vs 118±2mmHg; n≥17; P≤0.0001) and renal weights (390±8mg vs. 291±7mg; n≥17; P<0.05) than 1K/placebo mice, and more than double the number of CD45+ leukocytes in their kidneys. 1K/DOCA/salt-treated mice also displayed >2-fold increases in renal mRNA expression of pro-IL-18 and its receptor, IL-18R (n≥6; P<0.01), with the latter due partly to an increased number of IL-18R-expressing T cells within the kidneys (22039±3246 vs 2958±1100; n≥7; P< 0.001). Phenotypic profiling of IL-18R+ T cells revealed that they were an important source of IL-17 in the kidneys of 1K/DOCA/salt mice (P<0.05 vs IL-18R-T cells). T cell-dependent production of IL-17 was abolished in IL-18-/- mice (n=3-8; P<0.05) and this was associated with protection from the development of renal fibrosis and a blunted hypertensive response to 1K/DOCA/salt (122±3 vs 143±4mmHg in WT mice; n≥9; P≤0.001).
Conclusions: Experimental hypertension is associated with upregulation of IL-18 signalling in the kidney. IL-18 deficiency protected against renal T cell activation and fibrosis and the development of high BP, highlighting the IL-18 system as a potential target for future anti-hypertensive therapies.
Jordyn Thomas is a PhD student in the Vascular Biology and Immunopharmacology Group at La Trobe University. Her project aims to elucidate how inflammasome activation and subsequent production of IL-18 contributes to hypertension and chronic kidney disease. Although only 12 months into her candidature, Jordyn has already presented at a national conference, and she recently delivered an oral presentation at Experimental Biology 2018 (San Diego, USA). Jordyn has also written a comprehensive review on “The diagnostic and therapeutic potential of the IL-18 signalling pathway in chronic kidney disease” which is under consideration at the British Journal of Pharmacology.