Postconditioning with cyclosporine a reduces early renal dysfunction by inhibiting mitochondrial permeability transition
Résumé
BACKGROUND: Ischemia-reperfusion (IR) injury leads to mitochondrial permeability transition pore opening, which contributes to cell death. The aim of this study is to determine whether ischemic or pharmacological postconditioning with cyclosporine A (CsA) might protect the kidney from lethal reperfusion injury. METHODS: Male mice underwent a unilateral (right) nephrectomy followed by 30 minutes of contralateral (left) clamping of the renal artery. We studied 4 groups at 20 minutes and 24 hours of reperfusion: a sham group (n = 4), an ischemic group (n = 6), CsA-postconditioned group (postcond-CsA, injection of 3 mg/kg of CsA 5 minutes before the end of ischemia, (n = 6), and an ischemic postconditioning (IPC) group (n = 6), consisting of 3 cycles of 30 seconds of renal ischemia with 30 seconds intervening reperfusion. After 24 hours of reperfusion, we measured plasma creatinine, urea, and histological kidney injury. The kidney mitochondria were isolated to assess the mitochondria calcium retention capacity and oxidative phosphorylation. RESULTS: At 24 hours after reperfusion, serum creatinine decreased in postcond-CsA and IPC compared to ischemic group. The histological score was also significantly improved with postcond-CsA and IPC. At 20 minutes and 24 hours of reperfusion, calcium retention capacity was decreased significantly in the ischemic group. The mitochondrial respiration stay decreased in the ischemic group at 24 hours of reperfusion, whereas the respiration was improved significantly in the postcond-CsA and IPC group. Bax and cleaved caspase 3 decreased in PostCsA and IPC group. CONCLUSIONS: Our results suggest that IPC and CsA, administered immediately before reperfusion, protect the kidney from lethal injury.
Mots clés
Cyclosporine/*administration & dosage
Models
Mice
Urea/blood
Apoptosis/drug effects
Animals
Time Factors
Male
Biomarkers/blood
Mitochondrial Membrane Transport Proteins/*antagonists & inhibitors/metabolism
Cytoprotection
Oxidative Phosphorylation/drug effects
Creatinine/blood
Inbred BALB C
Immunosuppressive Agents/*administration & dosage
Kidney Transplantation/adverse effects/*methods
Ischemic Postconditioning/*methods
Kidney/*drug effects/metabolism/pathology/physiopathology/*surgery
Mitochondria/*drug effects/metabolism/pathology
Nephrectomy
Reperfusion Injury/metabolism/pathology/physiopathology/*prevention & control
Animal