title: Dual inhibiting senescence and epithelial-to-mesenchymal transition by erythropoietin preserve tubular epithelial cell regeneration and ameliorate renal fibrosis in unilateral ureteral obstruction.
abstract: This study aims to investigate the renoprotective effect of recombinant human erythropoietin (rhEPO) treatment could preserve tubular epithelial cell regeneration and ameliorate renal fibrosis by dual inhibition of stress-induced senescence and EMT in unilateral ureteric obstruction (UUO) mouse model. UUO or sham-operated mice were randomly assigned to receive rhEPO or vehicle treatment and were sacrificed on days 3, 7, and 14. Kidney specimens were fixed for histopathological and immunohistochemical study. The expression of S100A4, TGF-β1, BMP-7, Smad2/3, Smad1/5/8, and p16(INK4a) was determined by western blot and real-time RT-PCR. Vehicle treated UUO mice had increased tubular atrophy and interstitial fibrosis within 3 to 14 days. An increase in TGF-β1, Smad2/3, S100A4, and p16(INK4a) expression and a decrease in BMP-7 and Smad1/5/8 expression were observed in the obstructed kidneys. p16(INK4a) was positively correlated with TGF-β1/Smad2/3 and negatively correlated with BMP-7/Smad1/5/8 in UUO mice. rhEPO treatment significantly suppressed the upregulation of TGF-β, Smad2/3, S100A4, and p16(INK4a) and preserved the downregulation of BMP-7 and Smad1/5/8, resulting in markedly reduced TA/IF compared to the vehicle treated mice. The renoprotective effects of rhEPO could ameliorate renal TA/IF by modulating senescence and EMT which could be a part of therapeutic option in patients with chronic kidney disease.
authors.affiliation: Nephrology Unit, Department of Medicine, Faculty of Medicine, Thammasat University (Rangsit Campus), Khlong Nueng, Khlong Luang, Pathum Thani 12121, Thailand.
authors.forename: Adis
authors.initials: A
authors.lastname: Tasanarong
authors.affiliation: Division of Biochemistry, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University (Rangsit Campus), Khlong Nueng, Khlong Luang, Pathum Thani 12121, Thailand.
authors.forename: Supranee
authors.initials: S
authors.lastname: Kongkham
authors.affiliation: Department of Paediatric, Faculty of Medicine, Thammasat University (Rangsit Campus), Khlong Nueng, Khlong Luang, Pathum Thani 12121, Thailand.
authors.forename: Sookkasem
authors.initials: S
authors.lastname: Khositseth
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D004921:Erythropoietin / Q000494:pharmacology*; D005355:Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects* / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D055419:Bone Morphogenetic Protein 7; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011994:Recombinant Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D004921:Erythropoietin