Back to Search
Start Over
Anti-thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a DCD model
- Source :
- American Journal of Transplantation, American Journal of Transplantation, Wiley, 2010, 10 (1), pp.30-39. ⟨10.1111/j.1600-6143.2009.02924.x⟩
- Publication Year :
- 2010
- Publisher :
- HAL CCSD, 2010.
-
Abstract
- International audience; Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran (R) (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-beta (TGF-beta) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival.
- Subjects :
- Male
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences
Benzylamines
Pathology
Adenosine
[SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery
Swine
030232 urology & nephrology
030230 surgery
Kidney
Peritubular capillaries
chemistry.chemical_compound
0302 clinical medicine
Transforming Growth Factor beta
Fibrosis
Insulin
Immunology and Allergy
Pharmacology (medical)
direct thrombin inhibitor
ischemia reperfusion injury
[SDV.SA] Life Sciences [q-bio]/Agricultural sciences
Temperature
Organ Preservation
Glutathione
Tissue Donors
3. Good health
medicine.anatomical_structure
Tissue Plasminogen Activator
Models, Animal
Signal Transduction
kidney preservation
medicine.medical_specialty
Allopurinol
Organ Preservation Solutions
[SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery
Transplantation, Autologous
Article
03 medical and health sciences
Raffinose
interstitial fibrosis/tubular atrophy
Plasminogen Activator Inhibitor 1
medicine
Renal fibrosis
Animals
Humans
RNA, Messenger
Sirius Red
DNA Primers
Transplantation
Base Sequence
business.industry
graft function
Anticoagulants
Kidney metabolism
medicine.disease
Kidney Transplantation
CTGF
Oxidative Stress
chemistry
Chronic Disease
Azetidines
business
Reperfusion injury
Subjects
Details
- Language :
- English
- ISSN :
- 16006135 and 16006143
- Database :
- OpenAIRE
- Journal :
- American Journal of Transplantation, American Journal of Transplantation, Wiley, 2010, 10 (1), pp.30-39. ⟨10.1111/j.1600-6143.2009.02924.x⟩
- Accession number :
- edsair.doi.dedup.....ad5f194129061de54d3a0af280d73109