title: A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice.
abstract: Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany; Phenos GmbH, Hannover, Germany.
authors.forename: Nelli
authors.initials: N
authors.lastname: Shushakova
authors.affiliation: Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.affiliation: Diagnostic and Investigative Radiology, Hannover Medical School, Hannover, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hueper
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany; The kidney disease centre of the First Affiliated Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Rongjun
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany; Department of Gastrointestinal Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Exponential Biotherapies Inc., The Hague, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Wensvoort
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany; Phenos GmbH, Hannover, Germany; The Transplantation Center of the affiliated hospital, Zunyi Medical College, Zunyi, China.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy*; D064591:Allografts / Q000187:drug effects / Q000473:pathology*; D000818:Animals; D005260:Female; D016030:Kidney Transplantation / Q000009:adverse effects*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D012038:Regeneration; D015427:Reperfusion Injury / Q000188:drug therapy*; D014184:Transplantation, Homologous
chemical_list: D009842:Oligopeptides; C000604713:alanyl-glutaminyl-glycyl-valine