Postconditioning with cyclosporine a reduces early renal dysfunction by inhibiting mitochondrial permeability transition.

Abstract

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.

• Authors: Sandrine Lemoine, Bruno Pillot, Nicolas Rognant, Lionel Augeul, Maud Rayberin, Annie Varennes, Maurice Laville, Michel Ovize, Laurent Juillard
• Journal: Transplantation (Transplantation) Vol. 99 Issue 4 Pg. 717-23 (Apr 2015) ISSN: 1534-6080 [Electronic] United States
• PMID: 25793558 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Biomarkers
• Immunosuppressive Agents
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Cyclosporine
• Urea
• Creatinine

Topics

• Animals
• Apoptosis (drug effects)
• Biomarkers (blood)
• Creatinine (blood)
• Cyclosporine (administration & dosage)
• Cytoprotection
• Immunosuppressive Agents (administration & dosage)
• Ischemic Postconditioning (methods)
• Kidney (drug effects, metabolism, pathology, physiopathology, surgery)
• Kidney Transplantation (adverse effects, methods)
• Male
• Mice, Inbred BALB C
• Mitochondria (drug effects, metabolism, pathology)
• Mitochondrial Membrane Transport Proteins (antagonists & inhibitors, metabolism)
• Mitochondrial Permeability Transition Pore
• Models, Animal
• Nephrectomy
• Oxidative Phosphorylation (drug effects)
• Reperfusion Injury (metabolism, pathology, physiopathology, prevention & control)
• Time Factors
• Urea (blood)