Ghrelin protects against renal damages induced by angiotensin-II via an antioxidative stress mechanism in mice

Keiko Fujimura, Shu Wakino, Hitoshi Minakuchi, Kazuhiro Hasegawa, Koji Hosoya, Motoaki Komatsu, Yuka Kaneko, Keisuke Shinozuka, Naoki Washida, Takeshi Kanda, Hirobumi Tokuyama, Koichi Hayashi, Hiroshi Itoh

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25 Citations (Scopus)

Abstract

We explored the renal protective effects by a gut peptide, Ghrelin. Daily peritoneal injection with Ghrelin ameliorated renal damages in continuously angiotensin II (AngII)-infused C57BL/6 mice as assessed by urinary excretion of protein and renal tubular markers. AngII-induced increase in reactive oxygen species (ROS) levels and senescent changes were attenuated by Ghrelin. Ghrelin also inhibited AngII-induced upregulations of transforming growth factor-β (TGF-β) and plasminogen activator inhibitor-1 (PAI-1), ameliorating renal fibrotic changes. These effects were accompanied by concomitant increase in mitochondria uncoupling protein, UCP2 as well as in a key regulator of mitochondria biosynthesis, PGC1α. In renal proximal cell line, HK-2 cells, Ghrelin reduced mitochondria membrane potential and mitochondria-derived ROS. The transfection of UCP2 siRNA abolished the decrease in mitochondria-derived ROS by Ghrelin. Ghrelin ameliorated AngII-induced renal tubular cell senescent changes and AngII-induced TGF-β and PAI-1 expressions. Finally, Ghrelin receptor, growth hormone secretagogue receptor (GHSR)-null mice exhibited an increase in tubular damages, renal ROS levels, renal senescent changes and fibrosis complicated with renal dysfunction. GHSR-null mice harbored elongated mitochondria in the proximal tubules. In conclusion, Ghrelin suppressed AngII-induced renal damages through its UCP2 dependent anti-oxidative stress effect and mitochondria maintenance. Ghrelin/GHSR pathway played an important role in the maintenance of ROS levels in the kidney.

Original languageEnglish
Article numbere94373
JournalPloS one
Volume9
Issue number4
DOIs
Publication statusPublished - 2014 Apr 18

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Fujimura, K., Wakino, S., Minakuchi, H., Hasegawa, K., Hosoya, K., Komatsu, M., Kaneko, Y., Shinozuka, K., Washida, N., Kanda, T., Tokuyama, H., Hayashi, K., & Itoh, H. (2014). Ghrelin protects against renal damages induced by angiotensin-II via an antioxidative stress mechanism in mice. PloS one, 9(4), [e94373]. https://doi.org/10.1371/journal.pone.0094373