Leukocytic acetylcholine in chronic rejection of renal allografts
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Leukocytes, which accumulate in graft blood vessels during fatal acute rejection ofexperimental renal allografts, synthesise and release acetylcholine (ACh). In this study, Itested the hypothesis that ACh produced by leukocytes accumulating in graft blood vesselscontributes to the pathogenesis of chronic renal allograft vasculopathy (CAV).Kidneys were transplanted in the allogeneic Fischer 344 to Lewis rat strain combination.Isogeneic transplantations were performed in Lewis rats. Intravascular graft leukocytes wereinvestigated during an acute rejection episode on day 9 post-transplantation and during theprocess of vascular remodelling on day 42. The expression of essential elements for AChsynthesis and release was analysed by quantitative RT-PCR, Western blotting andimmunohistochemistry. Furthermore, renal allograft recipients were treated with rivastigmine,an ACh-esterase inhibitor, or placebo.Nine days after transplantation, numerous leukocytes accumulated in the blood vessels of theallograft (allograft: ~140 x 106; isograft: ~10 x 106). Leukocyte numbers decreased until day42 after allogeneic transplantation (allograft: ~40 x 106; isograft: ~10 x 106). Within 6 monthsafter transplantation, allografts developed typical hallmarks of chronic allograft injury -vascular remodelling, fibrosis, glomerular damage, tubular atrophy, and decreased renalfunction. The mRNA and protein expression of the high-affinity choline transporter wasupregulated in allograft leukocytes on day 9 and day 42. Choline acetyltransferase (ChAT)mRNA was detected only sporadically. However, increased amounts of ChAT protein weredetected in intravascular leukocytes from day 9 and 42 allografts compared with isografts.Carnitine acetyltransferase mRNA expression was increased in intravascular leukocytes fromday 42 allografts compared with other groups. ACh itself was present at about the same levelin leukocytes from isografts and allografts but absent in leukocytes from untreated kidneys.No vesicular acetylcholine transporter mRNA was detected but the mRNA of polyspecificorganic cation transporters 1, 2, and 3 was present in all samples. In line with the hypothesisthat endogenous ACh contributed to the pathogenesis of CAV, rivastigmine-treatmentenhanced the severity of experimental CAV.In conclusion, the results are in line with the hypothesis that leukocytic ACh contributes to thepathogenesis of CAV. The non-neuronal cholinergic system seems to be a promising target forthe development of novel therapeutic approaches preventing CAV.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler