title: Donor simvastatin treatment prevents ischemia-reperfusion and acute kidney injury by preserving microvascular barrier function.
abstract: Ischemia-reperfusion injury (IRI) after kidney transplantation may result in delayed graft function. We used rat renal artery clamping and transplantation models to investigate cholesterol-independent effects of clinically relevant single-dose peroral simvastatin treatment 2 h before renal ischemia on microvascular injury. The expression of HMG-CoA reductase was abundant in glomerular and peritubular microvasculature of normal kidneys. In renal artery clamping model with 30-min warm ischemia, simvastatin treatment prevented peritubular microvascular permeability and perfusion disturbances, glomerular barrier disruption, tubular dysfunction and acute kidney injury. In fully MHC-mismatched kidney allografts with 16-h cold and 1-h warm ischemia, donor simvastatin treatment increased the expression of flow-regulated transcription factor KLF2 and vasculoprotective eNOS and HO-1, and preserved glomerular and peritubular capillary barrier integrity during preservation. In vitro EC Weibel-Palade body exocytosis assays showed that simvastatin inhibited ischemia-induced release of vasoactive angiopoietin-2 and endothelin-1. After reperfusion, donor simvastatin treatment prevented microvascular permeability, danger-associated ligand hyaluronan induction, tubulointerstitial injury marker Kim-1 immunoreactivity and serum creatinine and NGAL levels, and activation of innate and adaptive immune responses. In conclusion, donor simvastatin treatment prevented renal microvascular dysfunction and IRI with beneficial effects on adaptive immune and early fibroproliferative responses. Further studies may determine potential benefits in clinical cadaveric kidney transplantation.
authors.affiliation: Cardiac Surgery, Heart and Lung Center, Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland. raimo.tuuminen@helsinki.fi
authors.forename: R
authors.initials: R
authors.lastname: Tuuminen
authors.forename: A I
authors.initials: AI
authors.lastname: Nykänen
authors.forename: P
authors.initials: P
authors.lastname: Saharinen
authors.forename: P
authors.initials: P
authors.lastname: Gautam
authors.forename: M A I
authors.initials: MA
authors.lastname: Keränen
authors.forename: R
authors.initials: R
authors.lastname: Arnaudova
authors.forename: E
authors.initials: E
authors.lastname: Rouvinen
authors.forename: H
authors.initials: H
authors.lastname: Helin
authors.forename: R
authors.initials: R
authors.lastname: Tammi
authors.forename: K
authors.initials: K
authors.lastname: Rilla
authors.forename: R
authors.initials: R
authors.lastname: Krebs
authors.forename: K B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D006085:Graft Survival / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007113:Immunity, Innate / Q000187:drug effects*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D055806:Microvessels / Q000187:drug effects*; D051381:Rats; D011920:Rats, Inbred WF; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D019821:Simvastatin / Q000627:therapeutic use*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin
keywords: Donor; ischemia-reperfusion-injury; kidney allograft; simvastatin; transplantation