title: Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction.
abstract: Chronic kidney disease (CKD) is associated with an increase in serum retinol; however, the underlying mechanisms of this disorder are poorly characterized. Here, we found that the alteration of hepatic metabolism induced the accumulation of serum retinol in 5/6 nephrectomy (5/6Nx) mice. The liver is the major organ responsible for retinol metabolism; accordingly, microarray analysis revealed that the hepatic expression of most CYP genes was changed in 5/6Nx mice. In addition, D-box-binding protein (DBP), which controls the expression of several CYP genes, was significantly decreased in these mice. Cyp3a11 and Cyp26a1, encoding key proteins in retinol metabolism, showed the greatest decrease in expression in 5/6Nx mice, a process mediated by the decreased expression of DBP. Furthermore, an increase of plasma transforming growth factor-β1 (TGF-β1) in 5/6Nx mice led to the decreased expression of the Dbp gene. Consistent with these findings, the alterations of retinol metabolism and renal dysfunction in 5/6Nx mice were ameliorated by administration of an anti-TGF-β1 antibody. We also show that the accumulation of serum retinol induced renal apoptosis in 5/6Nx mice fed a normal diet, whereas renal dysfunction was reduced in mice fed a retinol-free diet. These findings indicate that constitutive Dbp expression plays an important role in mediating hepatic dysfunction under CKD. Thus, the aggravation of renal dysfunction in patients with CKD might be prevented by a recovery of hepatic function, potentially through therapies targeting DBP and retinol.
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan, the Drug Innovation Research Center, Daiichi University of Pharmacy, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hamamura
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan, the Drug Innovation Research Center, Daiichi University of Pharmacy, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Ikeda
authors.affiliation: the Center for Sleep Medicine, Saiseikai Nagasaki Hospital, Katafuchi, Nagasaki 850-0003, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kondo
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Ikeyama
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Tokushige
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Itcho
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Furuichi
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Cell-Innovator Inc., EC Building, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Cell-Innovator Inc., EC Building, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Doi
authors.affiliation: the Department of Molecular Genetics, School of Medicine, Fukui University, Matsuoka, Fukui 910-1193, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Yokota
authors.affiliation: Neues Corporation, Tenyamachi-cho, Hakata-ku, Fukuoka 812-0025, Japan, and.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Amamoto
authors.affiliation: the Drug Innovation Research Center, Daiichi University of Pharmacy, Minami-ku, Fukuoka 815-8511, Japan, the Department of Molecular Biology, Daiichi University of Pharmacy, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Aramaki
authors.affiliation: the Integrated Center for Mass Spectrometry, Division of Membrane Biology, and Department of Evidence-based Laboratory Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Irino
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: From the Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8512, Japan, ohdo@phar.kyushu-u.ac.jp.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D000072516:Retinoic Acid 4-Hydroxylase; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014801:Vitamin A / Q000097:blood
chemical_list: D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; D008565:Membrane Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D014801:Vitamin A; D003577:Cytochrome P-450 Enzyme System; C000607080:Cyp26a1 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072516:Retinoic Acid 4-Hydroxylase
keywords: circadian clock; hepatocyte; renal physiology; retinol; transforming growth factor beta (TGF-beta)