Erythropoietin decreases renal fibrosis in mice with ureteral obstruction: role of inhibiting TGF-beta-induced epithelial-to-mesenchymal transition.
The inhibitory effects of recombinant human erythropoietin (rhEPO) were examined against (1) the progression of renal fibrosis in mice with complete unilateral ureteral obstruction and (2) the TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) in MDCK cells. Unilateral ureteral obstruction was induced in BALB/c mice and rhEPO (100 or 1000 U/kg, intraperitoneally, every other day) or vehicle was administered from day 3 to day 14. Immunoblotting and immunohistochemistry revealed increased expressions of TGF-beta1, alpha-smooth muscle actin (alpha-SMA), and fibronectin and decreased expression of E-cadherin in the obstructed kidneys. In contrast, rhEPO treatment significantly attenuated the upregulation of TGF-beta1 and alpha-SMA and the downregulation of E-cadherin. MDCK cells were treated with TGF-beta1 (5 ng/ml) for 48 h to induce EMT, and the cells were then co-treated with TGF-beta1 and rhEPO for another 48 h. Increased expressions of alpha-SMA and vimentin and decreased expressions of zona occludens-1 and E-cadherin were observed after TGF-beta1 treatment, and these changes were markedly attenuated by rhEPO co-treatment. TGF-beta1 increased phosphorylated Smad-2 expression in MDCK cells, which was decreased by rhEPO co-treatment. In conclusion, rhEPO treatment inhibits the progression of renal fibrosis in obstructed kidney and attenuates the TGF-beta1-induced EMT. It is suggested that the renoprotective effects of rhEPO could be mediated, at least partly, by inhibition of TGF-beta1-induced EMT.
Park
Sun-Hee
SH
Division of Nephrology and Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
Choi
Min-Jeong
MJ
Song
In-Kyung
IK
Choi
Soon-Youn
SY
Nam
Ju-Ock
JO
Kim
Chan-Duck
CD
Lee
Byung-Heon
BH
Park
Rang-Woon
RW
Park
Kwon Moo
KM
Kim
Yong-Jin
YJ
Kim
In-San
IS
Kwon
Tae-Hwan
TH
Kim
Yong-Lim
YL
D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000517:prevention & control; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*; D014517:Ureteral Obstruction / Q000473:pathology*
D000199:Actins; D005353:Fibronectins; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D004921:Erythropoietin