Nonerythropoietic derivative of erythropoietin protects against tubulointerstitial injury in a unilateral ureteral obstruction model.
BACKGROUND
Erythropoietin (EPO), a member of the cytokine type I superfamily, acts to increase circulating erythrocytes primarily by preventing apoptosis of erythroid progenitors, is known to protect tissues and can raise haemoglobin (Hb) concentrations. Recently, a second receptor for EPO comprising the EPO receptor and beta-common receptor has been reported to mediate EPO-induced tissue protection. EPO modified by carbamylation (CEPO) only signals through this second receptor. Accordingly, we hypothesized that treatment with CEPO, which would not increase Hb concentrations, would protect against tubular damage and thereby inhibit tubulointerstitial injuries.


METHODS
We evaluated therapeutic effects of CEPO using a rat unilateral ureteral obstruction model.


RESULTS
CEPO decreased tubular apoptosis and alpha-smooth muscle actin (alphaSMA) expression in the absence of polycythaemia, while the untreated obstructed kidneys exhibited increased tubular apoptosis with expanded (alphaSMA) expression. While EPO treatment similarly inhibited tubular apoptosis and alphaSMA expression, EPO treatment increased Hb concentrations and induced a wedge-shaped infarction.


CONCLUSIONS
We established a therapeutic approach using CEPO to protect against tubulointerstitial injury. The therapeutic value of this approach warrants further attention and preclinical studies.
Kitamura
Harumi
H
Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871 Japan.
Isaka
Yoshitaka
Y
Takabatake
Yoshitsugu
Y
Imamura
Ryoichi
R
Suzuki
Chigure
C
Takahara
Shiro
S
Imai
Enyu
E
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D000068817:Epoetin Alfa; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D006454:Hemoglobins / Q000378:metabolism; D007238:Infarction / Q000139:chemically induced; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D014517:Ureteral Obstruction / Q000188:drug therapy*
D000199:Actins; D006454:Hemoglobins; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D000068817:Epoetin Alfa