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. 2016 Oct 1;130(19):1727-39.
doi: 10.1042/CS20160183. Epub 2016 Jul 13.

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

Akiko Tanino  1 , Takafumi Okura  2 , Tomoaki Nagao  1 , Masayoshi Kukida  1 , Zuowei Pei  1 , Daijiro Enomoto  1 , Ken-Ichi Miyoshi  1 , Haruki Okamura  3 , Jitsuo Higaki  1
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Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice

Akiko Tanino et al. Clin Sci (Lond). .

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.

Keywords: aldosterone; interleukin-18; osteopontin; renal interstitial fibrosis.

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