title: 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.
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanino
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan okura@m.ehime-u.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Okura
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Nagao
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kukida
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Zuowei
authors.initials: Z
authors.lastname: Pei
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Daijiro
authors.initials: D
authors.lastname: Enomoto
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyoshi
authors.affiliation: Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
mesh_terms: D000450:Aldosterone / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D020382:Interleukin-18 / Q000172:deficiency* / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011188:Potassium / Q000008:administration & dosage; D012964:Sodium / Q000008:administration & dosage; D013148:Spironolactone / Q000008:administration & dosage
chemical_list: D020382:Interleukin-18; D053495:Osteopontin; D013148:Spironolactone; D000450:Aldosterone; D012964:Sodium; D011188:Potassium
keywords: aldosterone; interleukin-18; osteopontin; renal interstitial fibrosis