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A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney

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Abstract

Background

The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO.

Methods

To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks.

Results

CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining. Furthermore, PCR analysis demonstrated that TGF-β and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis.

Conclusion

We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.

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Authors and Affiliations

  1. Department of Urology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Ryoichi Imamura, Naotsugu Ichimaru, Toyofumi Abe, Masayoshi Okumi, Koji Yazawa & Norio Nonomura

  2. Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yoshitaka Isaka, Harumi Kitamura & Hiromi Rakugi

  3. Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Jyunya Kaimori & Shiro Takahara

  4. Department of Medicine, Division of Nephrology, Indiana University, 950 West Walnut Street, R2 202, Indianapolis, IN, 46202, USA

    Ruben M. Sandoval & Bruce A. Molitoris

Authors
  1. Ryoichi Imamura
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  2. Yoshitaka Isaka
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  3. Ruben M. Sandoval
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  4. Naotsugu Ichimaru
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  5. Toyofumi Abe
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  6. Masayoshi Okumi
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  7. Koji Yazawa
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  8. Harumi Kitamura
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  9. Jyunya Kaimori
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  10. Norio Nonomura
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  11. Hiromi Rakugi
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  12. Bruce A. Molitoris
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  13. Shiro Takahara
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Corresponding author

Correspondence to Yoshitaka Isaka.

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Imamura, R., Isaka, Y., Sandoval, R.M. et al. A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney. Clin Exp Nephrol 16, 852–862 (2012). https://doi.org/10.1007/s10157-012-0647-x

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  • DOI: https://doi.org/10.1007/s10157-012-0647-x

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