Objective: IL-18-deficient mice are protected from the development of 1-kidney deoxycorticosterone acetate and high salt (DOCA/salt)-induced blood pressure (BP) elevation, renal inflammation and injury. This study aimed to determine if pharmacological inhibition of IL-18 is similarly protective against DOCA/salt-induced hypertension and renal damage.
Methods: Male C57BL/6 mice were randomly assigned to receive either control IgG or anti-IL-18 neutralising monoclonal antibody (30 mg/kg, i.p., bolus every 3 days). Three days after the first injection, mice were uninephrectomised and treated for a further 21 days with either DOCA (2.4 mg/d, s.c. pellet) with high salt (0.9% in drinking water), or a placebo pellet (s.c.) plus normal drinking water. BP was measured weekly (tail-cuff, starting at baseline). Transdermal glomerular filtration rate (tGFR) measurements were recorded at baseline and at endpoint to determine kidney function. At post-mortem, kidneys were harvested to assess immune cell infiltration (flow cytometry), renal fibrosis and injury.
Results: Baseline systolic BP was not different between mice treated with anti-IL-18 mAb (118±2 mmHg) versus control IgG (122±3 mmHg). However, anti-IL-18 mAb treatment significantly blunted hypertensive responses to DOCA/salt, with systolic BP reaching 139±6 mmHg compared to 159±6 mmHg in control IgG-treated animals (n=11-12; P<0.05). Anti-IL-18 mAb treatment also significantly reduced DOCA/salt-induced leukocyte (CD45+) accumulation in the kidneys (0.9±0.1 x 105 cells/kidney) compared to control IgG treatment (1.6±0.3 x 105 cells/ kidney; n=11-12; P<0.05), which was largely attributed to reduced macrophage accumulation (CD11b+/F4/80+; n=11-12; P<0.05). A ~30% decline in kidney function (tGFR) was observed in DOCA/salt-treated mice that received control IgG, which appeared to be less severe in DOCA/salt-treated mice that received anti-IL-18 mAb (n=7). DOCA/salt-induced renal fibrosis and injury was unaffected by anti-IL-18 treatment.
Conclusions: IL-18 neutralisation affords protection against DOCA/salt-induced hypertension and renal inflammation. Thus, IL-18 may represent a potential therapeutic target to treat hypertension and chronic kidney disease.