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

Abstract

BackgroundThere 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.MethodsAll 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.ResultsMortality 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.ConclusionsOur 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.

Transcriptional trajectories of human kidney injury progression

“…Moreover, the presence of common elements in a nontransplant model expands the relevance of the human model beyond transplantation, indicating that the molecular processes described here are mostly independent of the peculiarities related to transplantation. However, multiple pharmacological effects of immunosuppressive drugs might influence the transcriptional response to kidney injury (35) and should be considered before the presented data can be generalized to a nontransplant setting. Figure 3E in comparison with other genes, reflecting the very early upregulation of EP300 along the transition to chronic kidney injury.…”

Tanshinone IIA Combined With CsA Inhibit Myocardial Cell Apoptosis Induced by Renal Ischemia-reperfusion Injury by Modulating Mitochondrial Function Through PI3K/Akt/Bad Pathway in Obese Rats 

“…Because CsA inhibited opening of the mPTP, it has been implicated as a treatment target at the beginning of reperfusion [40]. It is now widely believed that mitochondrial dysfunction (particularly opening of the mPTP) plays an important role aggravating injury following renal IRI [41]. Opening of the mPTP decreased the membrane potential and mitochondria swelling, which inhibited oxidative phosphorylation.…”

Effects of cyclosporine on ischemia-reperfusion injuries in rat kidneys. An experimental model

“…Our report involved the evaluation of validated measures and scales commonly used in the investigation of kidney injury, including measurements of plasma levels of creatinine 8 , 16 and urea 8 , as well as RIFLE criteria and histological analysis 2 , 14 , 16 . In summary, the results obtained herein were statistically equivalent with respect to each measure considered, with substantial consistency observed among the studied groups.…”

“…A very recent study shows a different result, suggesting that CsA protects against renal IRI in a dose-dependent manner, improving renal function and morphology, probably mediated by inhibition of mitochondrial permeability transition pore (mPTP), which would explain why the concentration of CsA has to be high at the time of reperfusion. This study used CsA injected at different times and with different doses, namely 3 mg.kg -1 , 1 hour or 10 minutes before 30 minutes ischemia or 10 mg.kg -1 , 10 minutes before the same ischemia pattern 16 . The same study points out the simplicity of pharmacological renal conditioning using different doses and timings of CsA injections whilst contributes importantly to a very sparse literature on this subject 8 , 11 , 17 .…”

“…A previous study performed in the USA evaluating differences between the use of CsA and a 20% lipid solution showed that, according to the dose-response curve, the latter proved more effective at preventing cardiac injury 6 in accordance with infarct area size. Taken together, it may be worth suggesting future studies endeavoring to evaluate CsA dose-response curves to be performed with the objective of elucidating whether cyclosporine is indeed unable to prevent renal injury, or whether methodological variability and study design are responsible for the controversial evidence presented with respect to different organs 11 , 16 , 17 .…”