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Expression of acetylcholine receptors by experimental rat renal allografts.

ABSTRACT: Chronic allograft injury (CAI) is a major cause for renal allograft dysfunction and characterized by vasculopathies, tubular atrophy, and fibrosis. We demonstrated that numerous leukocytes interact with vascular endothelial cells of allografts and produce acetylcholine, which contributes to vascular remodeling. The cholinergic system might be a promising target for the development of novel therapies. However, neither the cellular mechanisms nor the acetylcholine receptors involved in CAI are known. Kidney transplantation was performed in the Lewis to Lewis and in the Fischer-334 to Lewis rat strain combination, which is an established experimental model for CAI. Expression of nicotinic and muscarinic acetylcholine receptors mRNA was quantified in renal tissue by real-time RT-PCR on days 9 and 42 after surgery. We detected CHRNA2-7, CHRNA10, CHRNB2, CHRNB4, and CHRM1-3 mRNA in normal kidneys and in renal transplants. In contrast, CHRNA9, CHRM4, and CHRM5 mRNA remained below the threshold of detection. In renal allografts, CHRNA3 and CHRNB4 mRNA expression were dramatically reduced compared to isografts. In conclusion, we demonstrated that most acetylcholine receptor subtypes are expressed by normal and transplanted kidneys. Allograft rejection downmodulates CHRNA3 and CHRNB4 mRNA. The role of different acetylcholine receptor subtypes in the development of CAI remains to be established.

SUBMITTER: Meixner M

PROVIDER: S-EPMC4119892 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Expression of acetylcholine receptors by experimental rat renal allografts.

Meixner Marion M Atanasova Srebrena S Padberg Winfried W Grau Veronika V

BioMed research international 20140709

Chronic allograft injury (CAI) is a major cause for renal allograft dysfunction and characterized by vasculopathies, tubular atrophy, and fibrosis. We demonstrated that numerous leukocytes interact with vascular endothelial cells of allografts and produce acetylcholine, which contributes to vascular remodeling. The cholinergic system might be a promising target for the development of novel therapies. However, neither the cellular mechanisms nor the acetylcholine receptors involved in CAI are kno ...[more]

PMID: 25121092

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Project description:Ischemia/reperfusion injury (IRI) has a major impact on the long-term outcome of renal allografts. However, the mechanisms of IRI related to chronic allograft nephropathy (CAN) are still poorly understood. To address this issue, in a F344 to Lewis transplantation model of the rat, kidneys were either subjected to 20 min. or 24 hours of cold ischemia. A customized cDNA microarray representing 737 immune related genes was used for gene expression analysis after 12 hours and 6 months of engraftment. Thereby showing the 6-month graft function and histology were only moderately deteriorated following short cold ischemic time (20 min.), while prolonged ischemia (24 hrs) accelerated CAN development. Following prolonged cold ischemia already 12 hrs after engraftment about 30 genes were differentially expressed up to >20-fold. This included adhesion molecules, heat shock proteins, transcription factors and chemokines (CXCL10) associated with a strong CD68+ macrophage infiltration. Furthermore we observed a remarkable up-regulation of immunoproteasomes implying a re-organisation of the proteasome complex. This data might explain the higher incidence of alloreactivity following enhanced IRI. After 6 months, the prolonged cold ischemia of 24 hours revealed the significant induction of 4 genes: clusterin, C4, and the CCR7 ligands CCL19/21. This supported the observation of enhanced vasculopathy, humoral alloreactivity and increased tracking of MHC-II+ antigen presenting cells during CAN suggesting them as suitable novel targets for combating IRI. Keywords: transplantation, cold ischemia, inflammation, gene expression profiling Renal allografts from F344 donors were transplanted into unmodified LEW recipients. Before harvesting, grafts were perfused with University of Wisconsin solution at 4Â°C undergoing 20 min. (group A) or 24 hrs (group B) cold ischemia. Engrafted organs were either removed after 12 hrs (group I-A (n=3) and I-B (n=2)) or after 6 months (group II-A (n=3) and II-B (n=2)). Recipient animals of the group II received CyA treatment for 10 days at a dosage of 1.5 mg/kg. Untreated normal kidneys from F344 rats served as control. RNA from transplanted and untreated (control) rat kidneys were labeled by reverse transcription with Cy5 and Cy3 fluorescence, respectively.

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Expression of acetylcholine receptors by experimental rat renal allografts.

Publications

Expression of acetylcholine receptors by experimental rat renal allografts.

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