Abstract
BackgroundAcute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.MethodsMale rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined.ResultsTIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam).ConclusionWe used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.
Highlights
Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death
ejection fraction (EF), fractional shortening (FS) decreased in the IR and IR groups, in the IR group, compared with the sham group (p < 0.05), which was increased by pretreatment with Tanshinone IIA (TIIA), cyclosporine A (CsA), and TIIA+CsA (p < 0.05), pretreatment with TIIA+CsA was higher than TIIA and CsA (p < 0.05)
Left ventricular end-systolic internal diameter (LVIDs) and left ventricular end-diastolic internal diameter (LVIDd) increased in the IR and IR groups, in the IR group, compared with the sham group (p < 0.05), which was decreased by pretreatment with TIIA, CsA, and TIIA+CsA (p < 0.05), pretreatment with TIIA+CsA was lower than TIIA and CsA (p < 0.05) (Fig. 1b)
Summary
Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Diabetes and hyperuricaemia are closely related to obesity and can induce insulin resistance and hypertension, they are considered as chronic hyperinflammatory [3], which can increase the severity and incidence of renal diseases [4]. The mechanism of acute myocardial injury (AMI) induced by renal IR is indeterminate, including kidney dysfunction which results in a hyper-inflammatory state and volume overload [6]. The study has demonstrated that the IR mechanism is closely related with mitochondrial dysfunction in heart [8]. No study has explored mitochondrial dysfunction in myocardial cells induced by renal IR
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