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.
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Research Article|
August 23 2016
Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice
Akiko Tanino
;
Akiko Tanino
*
Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan
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Takafumi Okura
;
*
Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan
Correspondence: Dr Takafumi Okura (email okura@m.ehime-u.ac.jp)
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Tomoaki Nagao
;
Tomoaki Nagao
*
Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan
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Masayoshi Kukida
;
Masayoshi Kukida
*
Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan
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Zuowei Pei
;
Zuowei Pei
*
Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan
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Daijiro Enomoto
;
Daijiro Enomoto
*
Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan
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Ken-ichi Miyoshi
;
Ken-ichi Miyoshi
*
Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan
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Haruki Okamura
;
Haruki Okamura
†
Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Hyogo, Japan
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Jitsuo Higaki
Jitsuo Higaki
*
Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan
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Clin Sci (Lond) (2016) 130 (19): 1727-1739.
Article history
Received:
March 08 2016
Revision Received:
June 23 2016
Accepted:
July 13 2016
Accepted Manuscript online:
July 13 2016
Citation
Akiko Tanino, Takafumi Okura, Tomoaki Nagao, Masayoshi Kukida, Zuowei Pei, Daijiro Enomoto, Ken-ichi Miyoshi, Haruki Okamura, Jitsuo Higaki; Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice. Clin Sci (Lond) 1 October 2016; 130 (19): 1727–1739. doi: https://doi.org/10.1042/CS20160183
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