(Pro)renin receptor blocker improves survival of rats with sepsis

Yuki Hirano, Hiroya Takeuchi, Koichi Suda, Tomoko Hagiwara, Taku Miyasho, Yoshio Kawamura, Shingo Yamada, Takashi Oyama, Tsunehiro Takahashi, Norihito Wada, Yoshiro Saikawa, Atsuhiro Ichihara, Yuko Kitagawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background The renin-angiotensin system (RAS) affects inflammatory responses during sepsis. Nonproteolytic activation of prorenin by the (pro)renin receptor has recently been shown to stimulate the tissue RAS. In the present study, the effect of (pro)renin receptor blocker (PRRB) pretreatment on sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Materials and methods Male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: PRRB-treated group and control peptide-treated group. Survival was analyzed for 7 d after CLP. The serum concentrations of cytokines and high-mobility group box chromosomal protein 1 (HMGB1) were measured at three time points (0, 3, and 6 h after CLP). Hematoxylin-eosin staining and immunohistochemical staining for nonproteolytically activated prorenin and HMGB1 were performed on the cecum to assess pathologic changes found 6 h after CLP. Results Treatment with PRRB improved the survival rate of the post-CLP septic rats (P = 0.023). PRRB also significantly reduced serum tumor necrosis factor-α, interleukin-1β, and HMGB1 levels 6 h after CLP. In CLP rats that were treated with control peptide, the expression of activated prorenin was elevated in peritoneal foam cells. Moreover, expression of HMGB1 was increased in peritoneal inflammatory cells. In contrast, both were markedly suppressed in CLP rats that were treated with PRRB. Conclusions PRRB significantly improved the survival rate of rats with clinically relevant sepsis, possibly by attenuating a sepsis-induced systemic inflammatory response. We propose that overactivation of the RAS by activation of prorenin in foam cells may be a significant contributor to sepsis.

Original languageEnglish
Pages (from-to)269-277
Number of pages9
JournalJournal of Surgical Research
Volume186
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

    Fingerprint

Keywords

  • (Pro)renin receptor
  • Cecal ligation and puncture
  • Cytokine
  • Foam cell
  • High-mobility group box chromosomal protein 1
  • Prorenin
  • Renin-angiotensin system
  • Sepsis

ASJC Scopus subject areas

  • Surgery

Cite this

Hirano, Y., Takeuchi, H., Suda, K., Hagiwara, T., Miyasho, T., Kawamura, Y., Yamada, S., Oyama, T., Takahashi, T., Wada, N., Saikawa, Y., Ichihara, A., & Kitagawa, Y. (2014). (Pro)renin receptor blocker improves survival of rats with sepsis. Journal of Surgical Research, 186(1), 269-277. https://doi.org/10.1016/j.jss.2013.08.004