Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice

Abstract

Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18(-/-) and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury.

Inflammatory Cytokines as Uremic Toxins: “Ni Son Todos Los Que Estan, Ni Estan Todos Los Que Son”

“…IL-18 promotes tissue injury such as kidney fibrosis and vascular inflammation in preclinical studies [14,15]. In this regard, serum IL-18 predicted 2-year cardiovascular mortality in patients at various stages of CKD with a past history of acute myocardial infarction [16].…”

Micheliolide Attenuates Lipopolysaccharide-Induced Inflammation by Modulating the mROS/NF-κB/NLRP3 Axis in Renal Tubular Epithelial Cells

“…IL-18 is mainly produced by activated macrophages, which stimulate Th1 cells to secrete granulocyte-macrophage colony-stimulating factor, IFN- γ , and IL-2 and promote the proliferation of Th1 cells. IL-1 β and IL-18 can increase the expression of α -SMA protein in renal tubular epithelial cells, promote the transdifferentiation of renal tubular epithelial cells into myofibroblasts, and promote renal interstitial fibrosis [ 33 , 34 ]. Currently, the NLRP3 inflammasome is the most widely studied inflammasome.…”

Brucella abortus Infection Elicited Hepatic Stellate Cell-Mediated Fibrosis Through Inflammasome-Dependent IL-1β Production

“…In vitro studies have shown that IL-1β promotes the proliferation and myofibroblast transdifferentiation of HSCs with substantial increased levels of their fibrogenic markers (36)(37)(38). Activated caspase-1 could also cleave pro-IL-18 into its active form IL-18, and this cytokine has also been involved in fibrosis induction (38,39). In a murine model of non-alcoholic steatohepatitis, fibrosis was not reversed by IL-1Ra treatment, indicating that other regulators of NLRP3 inflammasome are involved in fibrogenesis promotion (33).…”