IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury During Deoxycorticosterone/Salt-Induced Hypertension in Mice
journal contribution
posted on 2025-05-20, 00:08 authored by Jordyn Thomas, Yeong H Ling, Brooke HuuskesBrooke Huuskes, Maria JelinicMaria Jelinic, Prerna Sharma, Narbada SainiNarbada Saini, Dorota M Ferens, Henry DiepHenry Diep, Shalini M Krishnan, Barbara K Kemp-Harper, Paul M O’Connor, Eicke Latz, Thiruma ArumugamThiruma Arumugam, Tomasz J Guzik, Michael J Hickey, Ashley MansellAshley Mansell, Christopher SobeyChristopher Sobey, Antony VinhAntony Vinh, Grant DrummondGrant DrummondIL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18-/- mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3+ T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18-/- mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18-/- mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits - interleukin-18 receptor 1 and IL-18R accessory protein - were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.
