aliskiren and Reperfusion-Injury

The aim of this study was to evaluate the effects of aliskiren, direct renin inhibitor, as an antioxidant and tissue protective agent and evaluate the molecular, biochemical, and histopathological changes in experimental ischemia and ischemia/reperfusion injury in rat ovaries. Forty-eight female rats were randomly divided into eight groups: in Group 1, only sham operation was performed. Group 2 received 100 mg/kg aliskiren and sham operated. In Group 3, 3 h-period of bilateral ovarian ischemia was applied. Group 4 received a 3-h period of ischemia followed by 3 h of reperfusion. Groups 5 and 6 received 50 and 100 mg/kg, respectively, of aliskiren and bilateral ovarian ischemia was applied (after a 3-h period of ischemia, both ovaries were surgically removed). To Groups 7 and 8, 50 and 100 mg/kg of aliskiren were administered, respectively, and the induction of ischemia was performed. At the end of a 3-h period of ischemia, bilateral vascular clips were removed, and 3 h of reperfusion continued. After the experiments, IL-1β, IL-6, TNF-α, and iNOS mRNA expressions and SOD, GSH, MDA, renin, and angiotensin-II levels were determined and histopathological changes were examined in rat ovaries. Aliskiren treatment normalized excessive changes in cytokine and oxidative stress markers in both ischemia and ischemia/reperfusion injury. Histopathologically, treatment with aliskiren ameliorated the development of ischemia and/or ischemia/reperfusion tissue injury. This study concluded that aliskiren treatment is effective in reversing ischemia and/or ischemia/reperfusion induced ovary damage via the improvement of oxidative stress, reduction of inflammation, and suppression of the renin-angiotensin aldosterone system.

Topics: Amides; Animals; Disease Models, Animal; Female; Fumarates; Ischemia; Ovarian Diseases; Protective Agents; Random Allocation; Rats; Rats, Wistar; Renin-Angiotensin System; Reperfusion Injury

To determine the protective effect of aliskiren on ischemia-reperfusion (I/R) injury in a rat renal (I/R) model.. Rats were randomly divided into five groups: sham control group; sham control with aliskiren pretreatment; I/R group and I/R with two doses of aliskiren pretreatment. Rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. Aliskiren (50 and 100 mg/kg) was administered orally by gavage 24 and 1 h prior to ischemia. After 24 h reperfusion, kidney samples were taken for the determination of malondialdehyde (MDA) level, superoxide dismutase (SOD), glutathione (GSH) activity and histological evaluation. The level of serum creatinine (SCR) and blood urea nitrogen (BUN), renin and angiotensin II (AT-2) was measured in serum samples.. Kidneys from I/R groups showed significant increase in MDA level and significant decrease in GSH, and SOD activity. IL-1β, iNOS and NFkB gene expression significantly increased in the I/R groups in the rat kidney tissue. Aliskiren treatment showed a significant down-regulatory effect on IL-1β, iNOS and NFkB mRNA expression. Compared with the sham group, SCR and BUN, renin and AT-2 were significantly increased in the I/R rats, accompanied by histopathological damage to the kidney.. Pretreatment with aliskiren ameliorated I/R-induced renal injury through decreasing nitric oxide and AT-2 levels and by the reduction of injury induced by I/R injury and ameliorated renal histopathological molecular and biochemical changes.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Creatinine; Fumarates; Kidney; Kidney Diseases; Male; Malondialdehyde; Microscopy, Electron; Nitric Oxide; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Renin; Reperfusion Injury; Superoxide Dismutase; Treatment Outcome

The purpose of this study was to investigate the effect of the renin inhibitor, aliskiren, on retinal ischemia-reperfusion injury. Retinal ischemia was induced by increasing intraocular pressure to 130 mmHg. At 7 days after ischemia, retinal damage was evaluated by measuring the retinal thickness and the number of retinal ganglion cells. Western blot was used to measure changes in the (pro)renin receptor expression. Retinal mRNA expressions of prorenin, angiotensinogen and angiotensin II type 1 receptor (AT1-R) were measured by real-time polymerase chain reaction. Rats were treated with the renin inhibitor, aliskiren. Although the number of retinal ganglion cells and the inner retinal thickness were significantly decreased at 7 days after ischemia, treatment with aliskiren significantly inhibited retinal ischemic injury. Administration of aliskiren increased mRNA expression of prorenin in the retina at 3 h after the reperfusion. The expression of the (pro)renin receptor was not changed after ischemia-reperfusion injury with or without aliskiren. Although there was an increase in the retinal expression of AT1-R at 3 h after the reperfusion, aliskiren administration suppressed this expression. A renin inhibitor attenuated subsequent ischemic damage in the rat retina via the inhibition of the prorenin-induced angiotensin generation.

Topics: Amides; Angiotensinogen; Animals; Blotting, Western; Cell Survival; Disease Models, Animal; Electroretinography; Fumarates; Infusion Pumps, Implantable; Intraocular Pressure; Male; Prorenin Receptor; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Reperfusion Injury; Retina; Retinal Diseases; Retinal Ganglion Cells; RNA, Messenger

The effect of blocking the first and rate-limiting step in renin-angiotensin cascade on the renal function in ischemia reperfusion injury has not been previously investigated. We investigated the effect of aliskiren, the first approved direct oral renin inhibitor, on the alterations in renal functional parameters in this condition. Wistar rats underwent left renal ischemia for 40 min. Group-1 received normal saline whereas Group-2 received aliskiren (30 mg/kg/day) by gavage for 6 days commencing one day before IRI. The hemodynamic and tubular functions and gene expression of neutrophil gelatinase-associated lipocalin (NGAL) and plasminogen activating inhibitor (PAI-1) in the right and left kidneys were measured five days following the IRI. Comparing Group-1 and Group-2, the left renal blood flow was significantly higher in Group-2 (1.28+/-0.36 vs. 0.39+/-0.05, P=0.007). Left kidney glomerular filtration rate was also higher in Group-2 but did not reach statistical significance (0.18+/-0.05 vs. 0.10+/-0.02, P=0.07). The left renal FE(Na) was significantly lower in Group-2 (29.9+/-6.4 vs. 49.7+/-7.8, P=0.03). Aliskiren also caused a significant decrease in the gene expression of both NGAL and PAI-1 in the left ischemic kidney. In conclusions, the administration of aliskiren before and after IRI appears to have ameliorated the IRI effect on the total renal artery blood flow, fractional excretion of sodium and gene expression of both NGAL and PAI-1 indicating a renoprotective effects in IRI.

Topics: Amides; Animals; Fumarates; Glomerular Filtration Rate; Kidney; Kidney Diseases; Male; Rats; Rats, Wistar; Renal Agents; Renal Circulation; Renin; Renin-Angiotensin System; Reperfusion Injury; Treatment Outcome

The protective effect of aliskiren on ischemia-reperfusion (I/R) injury in the heart and brain has been reported. Whether or not this protective effect extends into the alleviation of renal I/R injury is not known. Therefore, we investigated the protective effect of aliskiren in the kidney in this study. Sprague-Dawley rats were randomly divided into four groups: sham control group; sham control with aliskiren pretreatment; I/R group and I/R with aliskiren pretreatment. Aliskiren (3mg/kg) or vehicle was administrated intravenously via vena cava. Blood samples and the left kidneys were then collected to check for renal function, angiotensin II (Ang II), apoptosis and oxidative stress levels. Compared with the sham rats, serum creatinine (SCR) and blood urea nitrogen (BUN) were significantly increased in the I/R rats, accompanied by histopathological damage to the kidney, which included tubular cell swelling, desquamation, and cast formation. There were also more apoptotic cells and leukocyte infiltration in the I/R rats than in the sham rats. Pretreatment with aliskiren ameliorated I/R induced renal injury, i.e. reduced SCR and BUN levels, ameliorated renal histopathological changes, and decreased the apoptosis of cells and leukocyte infiltration in kidney. I/R injury also decreased superoxide dismutase (SOD) and glutathione (GSH-reduced form) levels, which were blocked with the aliskiren pretreatment. Aliskiren pretreatment exerts a protective effect on ischemia/reperfusion injury in the kidney, via amelioration of oxidative stress, and reduction in leukocyte infiltration and cellular apoptosis.

Topics: Amides; Animals; Apoptosis; Cytoprotection; Fumarates; Kidney; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Increasing evidence suggests that local renin-angiotensin system (RAS) plays an important role in cardiac diseases. Elevated p90 ribosomal S6 kinase (RSK) activity has been observed in diabetic animal, as well as in human failing hearts. We hypothesize that RSK mediates cardiac dysfunction by up regulating local RAS signaling. In the present study, we show that the prorenin mRNA level was significantly increased (~5.6-fold) in transgenic mouse hearts with cardiac specific expression of RSK (RSK-Tg). The RSK-Tg mice were more vulnerable to ischemia/reperfusion (I/R) injury than non-transgenic littermate controls (NLC). To further understand the direct contribution of cardiac renin to I/R injury, we used a Langendorff system to evaluate the effect of renin inhibition by aliskiren in RSK-Tg mouse hearts. In the vehicle-perfused group, I/R significantly decreased left ventricular developed pressure (LVDP) in RSK-Tg hearts compared to NLC (7% versus 60% of the baseline). However, aliskiren perfusion significantly increased LVDP in RSK-Tg (7% to 61%, p<0.01) but not in NLC hearts (60% to 62%, n.s.). The protective effect of aliskiren in RSK-Tg hearts was further demonstrated with positive (contraction) dp/dt (6.5% to 63%, p<0.01) and rate pressure product (RPP) (5% to 51%, p<0.01). Moreover, aliskiren significantly decreased I/R induced infarction in RSK-Tg (60% to 32%, p<0.01), compared to NLC hearts (37% to 32%, n.s.). These results suggest that RSK plays a crucial role in regulating local cardiac renin, which contributes to I/R induced cardiac injury and dysfunction. Thus, renin inhibition may provide an alternative therapeutic strategy under conditions of increased RAS.

Topics: Amides; Animals; Fumarates; Gene Expression Regulation; Heart; Mice; Mice, Transgenic; Myocardial Infarction; Myocardium; Renin; Renin-Angiotensin System; Reperfusion Injury; Ribosomal Protein S6 Kinases; RNA, Messenger

Angiotensin I-converting enzyme (ACE; kininase II) levels in humans are genetically determined. ACE levels have been linked to risk of myocardial infarction, but the association has been inconsistent, and the causality underlying it remains undocumented. We tested the hypothesis that genetic variation in ACE levels influences myocardial tolerance to ischemia. We studied ischemia-reperfusion injury in mice bearing 1 (ACE1c), 2 (ACE2c, wild type), or 3 (ACE3c) functional copies of the ACE gene and displaying an ACE level range similar to humans. Infarct size in ACE1c was 29% lower than in ACE2c (P<0.05). Pretreatment with a kinin B2 receptor antagonist suppressed this reduction. In ACE3c, infarct size was the same as in ACE2c. But ischemic preconditioning, which reduced infarct size in ACE2c (-63%, P<0.001) and ACE1c (-52%, P<0.05), was not efficient in ACE3c (-2%, NS, P<0.01 vs. ACE2c). In ACE3c, ischemic preconditioning did not decrease myocardial inflammation or cardiomyocyte apoptosis. Pretreatment with a renin inhibitor had no cardioprotective effect in ACE2c, but in ACE3c partially restored (38%) the cardioprotection of ischemic preconditioning. Thus, a modest genetic increase in ACE impairs myocardial tolerance to ischemia. ACE level plays a critical role in cardiac ischemia, through both kinin and angiotensin mediated mechanisms.

Topics: Amides; Angiotensin I; Angiotensin II; Animals; Apoptosis; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Fumarates; Heart; Kinins; Lung; Mice; Mice, Mutant Strains; Myocardial Infarction; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Renin; Reperfusion Injury