title: Endothelial progenitor cells homing and renal repair in experimental renovascular disease.
abstract: Tissue injury triggers reparative processes that often involve endothelial progenitor cells (EPCs) recruitment. We hypothesized that atherosclerotic renal artery stenosis (ARAS) activates homing signals that would be detectable in both the kidney and EPCs, and attenuated on renal repair using selective cell-based therapy. Pigs were treated with intrarenal autologous EPC after 6 weeks of ARAS. Four weeks later, expression of homing-related signals in EPC and kidney, single kidney function, microvascular (MV) density, and morphology were compared with untreated ARAS and normal control pigs (n = 7 each). Compared with normal EPC, EPC from ARAS pigs showed increased stromal cell-derived factor (SDF)-1, angiopoietin-1, Tie-2, and c-kit expression, but downregulation of erythropoietin (EPO) and its receptor. The ARAS kidney released the c-kit-ligand stem cell factor, uric acid, and EPO, and upregulated integrin beta2, suggesting activation of corresponding homing signaling. However, angiopoietin-1 and SDF-1/CXCR4 were not elevated. Administration of EPC into the stenotic kidney restored angiogenic activity, improved MV density, renal hemodynamics and function, decreased fibrosis and oxidative stress, and attenuated endogenous injury signals. The ARAS kidney releases specific homing signals corresponding to cognate receptors expressed by EPC. EPC show plasticity for organ-specific recruitment strategies, which are upregulated in early atherosclerosis. EPC are renoprotective as they attenuated renal dysfunction and damage in chronic ARAS, and consequently decreased the injury signals. Importantly, manipulation of homing signals may potentially allow therapeutic opportunities to increase endogenous EPC recruitment.
authors.affiliation: Divisions of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Chade
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Zhu
authors.forename: James D
authors.initials: JD
authors.lastname: Krier
authors.forename: Kyra L
authors.initials: KL
authors.lastname: Jordan
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Textor
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
mesh_terms: D000818:Animals; D002465:Cell Movement; D003251:Constriction, Pathologic / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology*; D005355:Fibrosis / Q000378:metabolism; D012078:Renal Artery Obstruction / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology*; D013552:Swine; D014945:Wound Healing