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Kidney Week

Abstract: FR-OR107

Osteocrin, a Bone-Derived Humoral Factor, Exerts a Renoprotective Role in Ischemia-Reperfusion Injury in Mice

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Nishiguchi, Yoshihiko, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Kuwabara, Takashige, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Umemoto, Shuro, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Fujimoto, Daisuke, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Kanki, Tomoko, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Hata, Yusuke, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Yokoi, Hideki, Kyoto University Graduate School of Medicine, Kyoto City, Japan
  • Izumi, Yuichiro, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Kakizoe, Yutaka, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Mukoyama, Masashi, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
Background

Natriuretic peptides (NPs; atrial, brain and C-type NPs: ANP, BNP and CNP) constitute the hormonal basis of the heart-kidney network, in which the remote organs influence each other under physiological and pathophysiological conditions. We recently reported that osteocrin (Ostn), originally identified as a secretory peptide in the bone and muscle, exerted bone elongation and cardioprotective effects through antagonizing NP clearance receptor NPR3. Of note, SNPs of the Ostn and NPPA/NPPB gene loci are reportedly related to a renal function decline risk by genome-wide association studies. However, the role of Ostn in the kidney has not been clarified yet.

Methods

To investigate the role of Ostn, we generated systemic Ostn knockout (KO) mice, and mated with liver-specific SAP promoter-driven Ostn-transgenic mice (KO-Tg). Wild-type (WT), KO and KO-Tg mice were subjected to ischemia-reperfusion injury (IRI) by unilateral renal artery clamping. Samples were collected at 3 weeks after IRI. Ostn expression in the kidney was evaluated by X-gal immunostaining using Ostn-LacZ knockin mice.

Results

In atrophic and fibrotic kidneys after IRI of WT, Ostn mRNA was increased in parallel with NPR3 and CNP upregulation, but not in the contralateral or pre-IRI kidneys. Furthermore, CNP expression was markedly suppressed in the contralateral kidney after IRI. These changes were either enhanced or suppressed in KO or KO-Tg, respectively, suggesting that Ostn affects the regulation of CNP and NPR3 expression in the kidney. In KO kidneys, mRNA expression of neutrophil gelatinase-associated lipocalin (NGAL) and IL-1b was further enhanced. In KO-Tg, fibrosis and atrophy were significantly ameliorated compared to WT and KO, together with the decreased expression of pro-fibrotic (aSMA, TGF-b), pro-inflammatory (IL-1b, TNFa) and tubular injury maker (NGAL, KIM-1) genes. X-gal immunostaining revealed that endogenous Ostn expression was induced by IRI in the tubular epithelial cells of corticomedullary junction in the kidney.

Conclusion

Exacerbation of IRI-induced kidney injury in Ostn-deficient mice was attenuated by ectopic overexpression of Ostn. Our data suggest a renoprotective role of Ostn, and could provide a potential therapeutic strategy against acute kidney injury.