Alterations of hepatic metabolism in chronic kidney disease via D-box-binding protein aggravate the renal dysfunction

Kengo Hamamura, Naoya Matsunaga, Eriko Ikeda, Hideaki Kondo, Hisako Ikeyama, Kazutaka Tokushige, Kazufumi Itcho, Yoko Furuichi, Yuya Yoshida, Masaki Matsuda, Kaori Yasuda, Atsushi Doi, Yoshifumi Yokota, Toshiaki Amamoto, Hironori Aramaki, Yasuhiro Irino, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4913-4927
Number of pages15
JournalJournal of Biological Chemistry
Volume291
Issue number10
DOIs
Publication statusPublished - Mar 4 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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