title: Acetylcholine and chronic vasculopathy in rat renal allografts.
abstract: BACKGROUND
  Chronic allograft vasculopathy (CAV) is an important aspect of chronic allograft injury, which limits the long-term success of renal transplantation. The pathogenesis of CAV is ill defined, and no effective therapies exist. Acute rejection episodes are a major risk factor for CAV. Recently, we demonstrated that leukocytes, which strongly accumulate in allograft blood vessels during fatal acute rejection, produce acetylcholine (ACh), which has the potential to provoke CAV. Herein, we test the hypothesis that ACh is also produced by leukocytes during the development of CAV.
  
  
  METHODS
  Kidneys were transplanted in the Fischer 344 to Lewis rat strain combination, an established experimental model for CAV. Isografts were performed in Lewis rats. The capacity of intravascular graft leukocytes to synthesize ACh was investigated during reversible acute rejection on day 9 posttransplantation and during the process of vascular remodeling on day 42. Furthermore, allograft recipients were treated with rivastigmine, which blocks enzymatic degradation of ACh.
  
  
  RESULTS
  The protein expression of the high-affinity choline transporter-1 and choline acetyltransferase was increased in leukocytes from allografts on day 9 and 42 posttransplantation. In addition, leukocytes accumulating in the lumina of allograft blood vessels were by far more numerous compared with isografts. In line with our hypothesis, ACh itself was detected by high-pressure liquid chromatography in graft leukocytes but not in leukocytes from untreated kidneys. Treatment with rivastigmine drastically exacerbated CAV compared with placebo.
  
  
  CONCLUSIONS
  We suggest that endogenous ACh contributes to the pathogenesis of CAV and may be a promising target for novel therapies preventing CAV.
authors.affiliation: Department of General and Thoracic Surgery, Laboratory of Experimental Surgery, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wilczynska
authors.forename: Uwe
authors.initials: U
authors.lastname: Pfeil
authors.forename: Anna
authors.initials: A
authors.lastname: Zakrzewicz
authors.forename: Hartmut
authors.initials: H
authors.lastname: Dietrich
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.forename: Andreas
authors.initials: A
authors.lastname: Hecker
authors.forename: Ignaz
authors.initials: I
authors.lastname: Wessler
authors.forename: Winfried
authors.initials: W
authors.lastname: Padberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
authors.forename: Veronika
authors.initials: V
authors.lastname: Grau
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D007668:Kidney / Q000098:blood supply; D016030:Kidney Transplantation; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D048448:Phenylcarbamates / Q000494:pharmacology; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D000068836:Rivastigmine; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D002800:Cholinesterase Inhibitors; D009419:Nerve Tissue Proteins; D048448:Phenylcarbamates; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C075746:Slc6a8 protein, rat; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine; D000068836:Rivastigmine