Lemoine Sandrine, Pillot Bruno, Augeul Lionel, Rabeyrin Maud, Varennes Annie, Normand Gabrielle, Baetz Delphine, Ovize Michel, Juillard Laurent
Université Lyon1, Inserm 1060CarMeN, Lyon, France.
Renal function unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
PLoS One. 2017 Aug 10;12(8):e0182358. doi: 10.1371/journal.pone.0182358. eCollection 2017.
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.
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.
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.
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.
有实验证据表明，致死性缺血再灌注损伤（IRI）主要是由于线粒体通透性转换孔（mPTP）开放所致，而环孢素A（CsA）可预防这种开放。我们研究的目的是表明，在缺血前即刻注射更高剂量的CsA（10mg/kg）或在缺血前更提前（1小时）注射更低剂量的CsA（3mg/kg）可保护肾脏并改善线粒体功能。
所有小鼠均接受右侧单侧肾切除术，随后夹闭左侧肾动脉30分钟。对照组小鼠未接受任何药物治疗。接受CsA治疗的三组小鼠在不同时间注射不同剂量的CsA，即在缺血前1小时或10分钟注射3mg/kg，或在缺血前10分钟注射10mg/kg。再灌注24小时后，测量血浆肌酐水平，评估组织学评分，并分离线粒体以计算钙保留能力（CRC）和氧化磷酸化水平。
CsA 10mg/kg-10分钟组和CsA 3mg/kg-1小时组的死亡率和肾功能显著高于CsA 3mg/kg-10分钟组。同样，前两组的CRC显著高于后一组，这表明肾功能的改善是由于mPTP开放的延迟时间更长。在受保护的组中，再灌注24小时后的氧化磷酸化水平也更高。
我们的结果表明，CsA提供的保护可能受到其可用性的限制。因此，注射的剂量和时间对于确保治疗有效至关重要，但这些发现可能在实际应用中具有挑战性。
