Abstract
Objective: Circulating levels of the pro inflammatory cytokine, interleukin18 (IL18), are elevated in patients with hypertension and chronic kidney disease (CKD). Moreover, genetic deficiency of IL18 prevents the development of one kidney deoxycorticosterone acetate and high salt (DOCA/salt) induced blood pressure (BP) elevation and renal injury. Thus, the current study aimed to determine if pharmacological inhibition of IL18 is similarly protective against elevations in BP, renal inflammation and dysfunction in the DOCA/salt model of hypertension and CKD. Design and method: Male C57BL/6 mice were randomly assigned to receive either control IgG or anti IL18 neutralising monoclonal antibody (control IgG and mAb; 30 mg/kg, i.p., Novartis, 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. Kidneys were harvested at endpoint for histopathological staining, quantitative reverse transcription PCR (RT qPCR) and flow cytometry to assess fibrosis, inflammation and immune cell infiltration, respectively. Results: Baseline systolic BP was not different between mice treated with anti IL18 mAb (118 ± 2 mmHg) versus control IgG (122 ± 3 mmHg). However, anti IL18 mAb treatment significantly blunted hypertensive responses to DOCA/salt, with systolic BP only reaching 139 ± 6 mmHg compared to 159 ± 6 mmHg in control IgG treated animals (Figure; n = 11–12; P < 0.05). Anti IL18 mAb treatment also significantly reduced DOCA/salt induced leukocyte (CD45+) accumulation in the kidneys (0.9 ± 0.1x105 cells/kidney) compared to control IgG treatment (1.6 ± 0.3x105 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 was observed in DOCA/salt-treated mice that received control IgG, which was associated with renal fibrosis and injury. Impaired kidney function decline (but not fibrosis and injury) appeared to be less severe in DOCA/salt treated mice that received anti IL18 mAb (n = 7). DOCA/salt treatment increased expression of genes associated with renal fibrosis (Col1al, Col3a1 and Col5a1), injury (Kim1 and Ngal) and inflammation (Ifng, Mrc1, II6, Ccl2 etc.). Surprisingly, DOCA/salt induced changes in gene expression were not prevented by anti IL18 mAb treatment. Conclusions: IL18 neutralisation affords protection against DOCA/salt induced hypertension and renal inflammation. Thus. IL18 may represent a potential therapeutic target to treat hypertension and CKD.
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