title: Cell therapy with human renal cell cultures containing erythropoietin-positive cells improves chronic kidney injury.
abstract: New therapeutic strategies for chronic kidney disease (CKD) are necessary to offset the rising incidence of CKD and donor shortage. Erythropoietin (EPO), a cytokine produced by fibroblast-like cells in the kidney, has recently emerged as a renoprotective factor with anti-inflammatory, antioxidant properties. This study (a) determined whether human renal cultures (human primary kidney cells [hPKC]) can be enriched in EPO-positive cells (hPKC(F+)) by using magnetic-bead sorting; (b) characterized hPKC(F+) following cell separation; and (c) established that intrarenal delivery of enriched hPKC(F+) cells would be more beneficial in treatment of renal injury, inflammation, and oxidative stress than unsorted hPKC cultures in a chronic kidney injury model. Fluorescence-activated cell sorting analysis revealed higher expression of EPO (36%) and CD73 (27%) in hPKC(F+) as compared with hPKC. After induction of renal injury, intrarenal delivery of hPKC(F+) or hPKC significantly reduced serum creatinine, interstitial fibrosis in the medulla, and abundance of CD68-positive cells in the cortex and medulla (p < .05). However, only hPKC(F+) attenuated interstitial fibrosis in the renal cortex and decreased urinary albumin (3.5-fold) and urinary tubular injury marker kidney injury molecule 1 (16-fold). hPKC(F+) also significantly reduced levels of renal cortical monocyte chemotactic protein 1 (1.8-fold) and oxidative DNA marker 8-hydroxy-deoxyguanosine (8-OHdG) (2.4-fold). After 12 weeks, we detected few injected cells, which were localized mostly to the cortical interstitium. Although cell therapy with either hPKC(F+) or hPKC improved renal function, the hPKC(F+) subpopulation provides greater renoprotection, perhaps through attenuation of inflammation and oxidative stress. We conclude that hPKC(F+) may be used as components of cell-based therapies for degenerative kidney diseases.
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
authors.forename: Liliya M
authors.initials: LM
authors.lastname: Yamaleyeva
authors.forename: Nadia K
authors.initials: NK
authors.lastname: Guimaraes-Souza
authors.forename: Louis S
authors.initials: LS
authors.lastname: Krane
authors.forename: Sigrid
authors.initials: S
authors.lastname: Agcaoili
authors.forename: Kenneth
authors.initials: K
authors.lastname: Gyabaah
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.forename: Tamer
authors.initials: T
authors.lastname: Aboushwareb
authors.forename: James J
authors.initials: JJ
authors.lastname: Yoo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002469:Cell Separation; D064987:Cell- and Tissue-Based Therapy; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007668:Kidney / Q000166:cytology* / Q000293:injuries / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011923:Rats, Nude; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D004921:Erythropoietin