A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney.
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.


CONCLUSIONS
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.
Department of Urology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Ryoichi
R
Imamura
Yoshitaka
Y
Isaka
Ruben M
RM
Sandoval
Naotsugu
N
Ichimaru
Toyofumi
T
Abe
Masayoshi
M
Okumi
Koji
K
Yazawa
Harumi
H
Kitamura
Jyunya
J
Kaimori
Norio
N
Nonomura
Hiromi
H
Rakugi
Bruce A
BA
Molitoris
Shiro
S
Takahara
D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D005355:Fibrosis; D006454:Hemoglobins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D024042:Collagen Type I; D006454:Hemoglobins; D016212:Transforming Growth Factor beta; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D003404:Creatinine