Dose and timing of injections for effective cyclosporine A pretreatment before renal ischemia reperfusion in mice

PLoS One. 2017 Aug 10;12(8):e0182358. doi: 10.1371/journal.pone.0182358. eCollection 2017.

Abstract

Background: There is experimental evidence that lethal ischemia-reperfusion injury (IRI) is largely due to mitochondrial permeability transition pore (mPTP) opening, which can be prevented by cyclosporine A (CsA). The aim of our study is to show that a higher dose of CsA (10 mg/kg) injected just before ischemia or a lower dose of CsA (3 mg/kg) injected further in advance of ischemia (1 h) protects the kidneys and improves mitochondrial function.

Methods: All mice underwent a right unilateral nephrectomy followed by 30 min clamping of the left renal artery. Mice in the control group did not receive any pharmacological treatment. Mice in the three groups treated by CsA were injected at different times and with different doses, namely 3 mg/kg 1 h or 10 min before ischemia or 10 mg/kg 10 min before ischemia. After 24 h of reperfusion, the plasma creatinine level were measured, the histological score was assessed and mitochondria were isolated to calculate the calcium retention capacity (CRC) and level of oxidative phosphorylation.

Results: Mortality and renal function was significantly higher in the CsA 10 mg/kg-10 min and CsA 3mg/kg-1 h groups than in the CsA 3mg/kg-10 min group. Likewise, the CRC was significantly higher in the former two groups than in the latter, suggesting that the improved renal function was due to a longer delay in the opening of the mPTP. Oxidative phosphorylation levels were also higher 24 h after reperfusion in the protected groups.

Conclusions: Our results suggest that the protection afforded by CsA is likely limited by its availability. The dose and timing of the injections are therefore crucial to ensure that the treatment is effective, but these findings may prove challenging to apply in practice.

MeSH terms

  • Acute Kidney Injury / prevention & control*
  • Animals
  • Calcineurin Inhibitors / administration & dosage*
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Cyclosporine / administration & dosage*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Evaluation, Preclinical
  • Kidney / blood supply*
  • Kidney / drug effects
  • Kidney / pathology
  • Male
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Reperfusion Injury / prevention & control*

Substances

  • Calcineurin Inhibitors
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Cyclosporine
  • Calcium

Grants and funding

The authors received no specific funding for this work.