A Crucial Role for Interleukin‐18/IL‐18R Signalling Axis in the Development of Renal Inflammation and Elevated Blood Pressure in 1 Kidney/DOCA/Salt‐Induced Hypertension
Authors: Thomas Jordyn Michele , Ling Yeong Hann , Krishnan Shalini Murali , Ferens Dorota , Masters Seth , Kemp‐Harper Barbara , Mansell Ashley , Sobey Christopher , Vinh Antony , Drummond Grant 
Published: June 2021

Interleukin‐18 (IL‐18) is a pro‐inflammatory cytokine released downstream of inflammasome activation that is elevated in hypertensive patients. However, whether IL‐18 plays a causal role in hypertension is unknown. The aims of the current study are to characterise renal expression of IL‐18 and its receptor (IL‐18R) in hypertensive mice, and to determine the effect of IL‐18 and IL‐18R deficiency on the development of hypertension and renal inflammation. Hypertension was induced in male wild‐type (WT), RAG1−/− 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). Control mice received uninephrectomy, a placebo pellet and normal drinking water (1K/placebo). RAG1−/− mice received either PBS, WT or IL‐18R−/− T cells via tail vein three weeks before 1K/DOCA/salt treatment. Blood pressure (BP) was measured via tail cuff. After 21 days, kidneys were harvested to assess: hypertrophy; mRNA expression of IL‐18, IL‐18R (qRT‐PCR); and immune cell numbers and cellular expression of IL‐18R (flow cytometry). BP and kidney weight were significantly elevated in 1K/DOCA/salt treated mice (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 promoted renal inflammation, indicated by a 2‐fold increase in CD45+ leukocytes. There was a marked increase (i.e. >2‐fold) in renal expression of pro‐IL‐18 and its receptor, IL‐18R, in 1K/DOCA/salt‐ versus 1K/placebo‐treated mice (n≥6; P<0.01). Regarding the latter findings, flow cytometric analysis of kidney cell suspensions demonstrated that the increase in IL‐18R in the kidneys of 1K/DOCA/salt‐treated mice was primarily due to an influx of IL‐18R‐expressing T cells. Intracellular cytokine analyses of these renal T cells revealed that 1K/DOCA/salt treatment increased IL‐17 production in IL‐18R+ T cells, but not in IL‐18R‐ T cells. Importantly, IL‐18−/− mice were profoundly protected from the hypertensive actions of 1K/DOCA/salt compared to WT mice (119±6 vs 145±6 mmHg; n=5, P<0.05). The increase in IL‐17 production by IL‐18R+ T cells following 1K/DOCA/salt treatment was also abolished IL‐18−/− mice. Moreover, adoptive transfer of IL‐18R−/− T cells did not fully restore the hypertensive response in 1K/DOCA/salt‐treated RAG1−/− mice. To conclude, 1K/DOCA/salt‐induced hypertension is associated with upregulation of the IL‐18 and IL‐18R signalling system in the kidney. IL‐18 deficiency protects against the development of high BP and renal inflammation in 1K/DOCA/salt‐induced hypertension, highlighting the IL‐18 system as a potential target for future anti‐hypertensive therapies.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.