A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney

Ryoichi Imamura, Yoshitaka Isaka, Ruben M. Sandoval, Naotsugu Ichimaru, Toyofumi Abe, Masayoshi Okumi, Koji Yazawa, Harumi Kitamura, Jyunya Kaimori, Norio Nonomura, Hiromi Rakugi, Bruce A. Molitoris, Shiro Takahara

Research output: Contribution to journalArticle

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)852-862
Number of pages11
JournalClinical and Experimental Nephrology
Issue number6
StatePublished - Dec 1 2012



  • Apoptosis
  • Carbamylated erythropoietin
  • Remnant kidney
  • TGF-β

ASJC Scopus subject areas

  • Nephrology
  • Physiology
  • Physiology (medical)

Cite this

Imamura, R., Isaka, Y., Sandoval, R. M., Ichimaru, N., Abe, T., Okumi, M., Yazawa, K., Kitamura, H., Kaimori, J., Nonomura, N., Rakugi, H., Molitoris, B. A., & Takahara, S. (2012). A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney. Clinical and Experimental Nephrology, 16(6), 852-862. https://doi.org/10.1007/s10157-012-0647-x