The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity

Adriamycin (ADR) is commonly used for many solid tumor treatments. Its clinical utility is, however, largely limited by the adverse reactions, are known to be nephrotoxic. The mechanism by which it induces kidney damage is still not completely understood, but its nephrotoxicity might relate to increase reactive oxidant status (ROS), mitochondrial dysfunction. Until now, neurohormonal activation of it is unclear. ADR might activate the renin angiotensin system. Angiotensin-II also induced ROS and mitochondrial dysfunction. The aim of this study was to investigate whether angiotensin-II production inhibition has the protective effect on attenuation of mitochondrial function in rats with acute ADR-nephrotoxicity or not. Rats were divided into five groups as a control, ADR, co-treated ADR with captopril (CAP), co-treated ADR with Aliskren, co-treated ADR with both CAP and Aliskren groups. Creatinine kinase (CK) levels were measured at the end of treatment period. The kidneys were homogenized and biochemical measurements were made in mitochondria, cytosol. Mitochondria membrane potential (MMP) and ATP levels were determined. ADR increased CK levels and oxidative stress in mitochondria too (p<0.05). ADR significantly decreased MMP and ATP level in kidney mitochondria (p<0.05). Co-administration with ADR and Aliskren and CAP improved the dissipation of MMP (p<0.05). The decrease in ATP level was restored by treatment with inhibitors of ACE and renin. We concluded that inhibitors of angiotensin-II are effective against acute ADR induced nephrotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo

THE ROLE OF ANGIOTENSIN ON MITOCHONDRIAL ATP PRODUCTION AND THE EFFECT OF ANGIOTENSIN ON ADRIAMYCIN-INDUCED CARDIOMYOPATHY

Background: Adriamycin increases reactive oxygen species and this leads to diminish mitochondrial function. Angiotensin-II stimulates mitochondrial-ROS generation. It was aimed to examine whether the diminishing mitochondrial energy production induced by ADR is attenuated by rennin-angiotensin inhibitors. Methods: Rats were divided into five groups. The control group was treated with normal saline. Adriamycin was administered to the second group at a dose of 4 mg/kg i.p every other 2 days. Captopril were administered to the third group at a dose 10 mg/kg plus ADR. Aliskiren was administered to the fourth group at a dose 50 mg/kg plus ADR. Captopril, Aliskiren and ADR were administered to the last group at the same dose. Captopril and aliskiren were gavage administration daily for 8 times. Left ventricular functions, ECG variables and blood pressure were assessed at the end of injection period. Mitochondrial ATP levels were determined. Results: Only ADR treated animals had a decrease in the left ventricular developed pressure, a decrease in the maximal rate of the increased pressure, and an increase in the left ventricular end-diastolic pressure. ADR increased ST interval and decreased mean blood pressure. ADR decreased ATP level in myocyte mitochondria. By maintaining normal levels of mitochondrial ATP, captopril and aliskiren treatment prevented the changes in ECG, blood pressure and left ventricular function.Conclusions: We concluded that inhibitors of ACE and renin could be effective against ADR cardiotoxicity via the restoration of ATP production and prevention of mitochondrial damage in vivo.Key words: Adriamycin, Mitochondrial AT

Adriamycin-Induced Mitochondrial Toxicity in Rat Heart is Exacerbate by Angiotensin

Adriamycin (ADR) increases the production of reactive oxygen species, which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial-ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors (captopril and/or aliskiren) protect against ADR-induced mitochondrial function impairment.Rats were divided into five groups (n=14 each). The control group was treated with saline. ADR was administered to the four other groups every 2 days (4 mg/kg i.p). One of these was co-administered captopril (10 mg/kg/daily) and the other was co-treated with aliskiren (50 mg/kg/daily), while another was co-treated with both captopril and aliskiren (captopril and aliskiren were gavage administration daily for 8 days). Left ventricular function, ECG variables and blood pressure were assessed at the end of treatment period. The hearts were homogenized and biochemical measurements were made in mitochondria, cytosol and plasma. Mitochondria membrane potential (MMP), ATP levels were determined.ADR decreased in the left ventricular developed pressure (LVDP), the maximal rate of rise of pressure (+dP/dt), and increased in the left ventricular end-diastolic pressure (LVEDP). ADR increased ST interval and decreased mean blood pressure. ADR increased oxidative stress in mitochondrial, cytosolic and plasma. ADR decreased MMP and ATP level in myocyte mitochondria. ADR co-administration with renin and ACE inhibitors improved the dissipation of MMP. The decreased in ATP level was restored by treatment with inhibitors of ACE and renin. By maintaining normal levels of mitochondrial MMP and ATP, captopril and aliskiren treatment prevented the pathologic changes in ECG, blood pressure and left ventricular function.We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.</p

Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II

Adriamycin (ADR) increases the production of reactive oxygen species (ROS), which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors protect against ADR-induced mitochondrial function impairment. Rats were divided into five groups as control, ADR, co-treatment ADR with captopril, co-treatment ADR with aliskiren, co-treatment ADR with both captopril and aliskiren. Left ventricular function and blood pressures were assessed at the end of treatment period. Mitochondrial membrane potential (MMP) and ATP levels were determined. ADR treatment decreased the left ventricular pressure and increased the left ventricular end-diastolic pressure. ADR decreased MMP and ATP levels in myocyte mitochondria due to increasing oxidative stress. ADR decreased MMP and ATP levels due to increased oxidative stress in the heart. Inhibitors of ACE and renin caused the elevation of the decreased of MMP and ATP levels. The pathologic changes in electrocardiogram, blood pressure and left ventricular function were decreased by inhibition of Ang-II production. We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.Abstract Adriamycin (ADR) increases the production of reactive oxygen species (ROS), which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors protect against ADR-induced mitochondrial function impairment.Rats were divided into five groups as control, ADR, co-treatment ADR with captopril, co-treatment ADR with aliskiren, co-treatment ADR with both captopril and aliskiren. Left ventricular function and blood pressures were assessed at the end of treatment period. Mitochondrial membrane potential (MMP) and ATP levels were determined. ADR treatment decreased the left ventricular pressure and increased the left ventricular end-diastolic pressure. ADR decreased MMP and ATP levels in myocyte mitochondria due to increasing oxidative stress. ADR decreased MMP and ATP levels due to increased oxidative stress in the heart. Inhibitors of ACE and renin caused the elevation of the decreased of MMPand ATP levels. The pathologic changes in electrocardiogram, blood pressure and left ventricular function were decreased by inhibition of Ang-II production. We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.&nbsp;</div