期刊
CLINICAL SCIENCE
卷 130, 期 19, 页码 1727-1739出版社
PORTLAND PRESS LTD
DOI: 10.1042/CS20160183
关键词
aldosterone; interleukin-18; osteopontin; renal interstitial fibrosis
资金
- Actelion Pharmaceuticals Japan
- Astellas Pharma Inc.
- Beringer-Ingerheim Japan Co.
- Daiichi-Sankyo Inc.
- Sumitomo Dainippon Pharma
- Kyowa Hakkoh Kirin Co.
- MSD Co.
- Mitsubishi Tanabe Co.
- Mochida Pharmaceutical Co. Ltd.
- Otsuka Pharmaceutical Co Ltd
- Sanofi Aventis Co.
- Pfizer Health Care Inc.
- Shionogi Pharm Co. Ltd
- Takeda Pharma Co., Ltd.
Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon gamma-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.
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