Effect Of Direct Renin Inhibitor Research Articles

MP53-20 RENOPROTECTIVE EFFECT OF DIRECT RENIN INHIBITOR (ALISKIREN) DURING ACUTE AND CHRONIC PARTIAL URETERAL OBSTRUCTION IN RAT SOLITARY KIDNEY

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Ureter (including Pyeloplasty) and Bladder Reconstruction (including fistula), Augmentation, Substitution, Diversion II (MP53)1 Sep 2021MP53-20 RENOPROTECTIVE EFFECT OF DIRECT RENIN INHIBITOR (ALISKIREN) DURING ACUTE AND CHRONIC PARTIAL URETERAL OBSTRUCTION IN RAT SOLITARY KIDNEY Mohamed Essam, Nashwa Barakat, Ahmed Elkashef, Amira Awadalla, A. E. Behery, and Mahmoud Abdel-Maboud Mohamed EssamMohamed Essam More articles by this author , Nashwa BarakatNashwa Barakat More articles by this author , Ahmed ElkashefAhmed Elkashef More articles by this author , Amira AwadallaAmira Awadalla More articles by this author , A. E. BeheryA. E. Behery More articles by this author , and Mahmoud Abdel-MaboudMahmoud Abdel-Maboud More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002083.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Obstructive uropathy is a major clinical problem that can result in permanent renal damage. The renoprotective effect of direct renin inhibitor (aliskiren) has been demonstrated in many experimental animal models mainly renal ischemia/reperfusion injury. Therefore, we studied the effect of aliskiren on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. METHODS: 60 male Sprague–Dawley rats were randomly allocated into 3 groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. 10 rats from each group were sacrificed after 2 weeks, while the remaining rats were sacrificed after 4 weeks. Left kidneys were harvested for histopathological examination, BCL-2, IL-6, TGF-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. RESULTS: After 2 and 4 weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration (table 1). Aliskiren group showed significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin gene expression (table 2). Aliskiren also significantly increased GSH and SOD activity and reduced MDA and NO activity (table 2). Moreover, aliskiren administration for 4 weeks after PUO significantly yielded more renoprotective effect compared to its administration for 2 weeks. CONCLUSIONS: Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e947-e947 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mohamed Essam More articles by this author Nashwa Barakat More articles by this author Ahmed Elkashef More articles by this author Amira Awadalla More articles by this author A. E. Behery More articles by this author Mahmoud Abdel-Maboud More articles by this author Expand All Advertisement Loading ...

Renoprotective effect of direct renin inhibitor (aliskiren) during partial ureteral obstruction

Partial ureteral obstruction (PUO) is a major clinical problem in the daily urologic practice that is treatable and often reversible. Renin-angiotensin system (RAS) is implicated in the pathophysiology of PUO as angiotensin II induces alterations in renal hemodynamics, apoptosis, inflammation and fibrosis

Functional and molecular evaluation of using aliskiren during acute and chronic partial ureteral obstruction in rat solitary kidney

AimsTo study the effect of direct renin inhibitor (aliskiren) on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. Main methodsSixty male Sprague–Dawley rats were randomly allocated into three groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. Ten rats from each group were sacrificed after two weeks, while the remaining rats were sacrificed after four weeks. Left kidneys were harvested for histopathological examination, BCL-2, interleukin (IL)-6, transforming growth factor (TGF)-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. Key findingsAfter two and four weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration. Aliskiren group showed statistically significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin relative gene expression. Aliskiren significantly increased GSH and SOD activity and reduced MDA and NO activity. Moreover, aliskiren administration for four weeks after PUO significantly yielded more renoprotective effect compared to its administration for two weeks. SignificanceAliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney.

Comparative Effects of Direct Renin Inhibitor and Angiotensin Receptor Blocker on Albuminuria in Hypertensive Patients with Type 2 Diabetes. A Randomized Controlled Trial

BackgroundIn patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.MethodsWe randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria.ResultsTwelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients.ConclusionDRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen.

Renoprotective effects of aliskiren on adenine-induced tubulointerstitial nephropathy: possible underlying mechanisms.

The present study investigated the possible renoprotective effect of direct renin inhibitor (aliskiren) on renal dysfunctions, as well as its underlying mechanisms in rat model of adenine-induced tubulointerstitial nephropathy. Forty male Sprague-Dawley rats were randomized into 4 groups; normal group, aliskiren group (normal rats received 10 mg/kg aliskiren), adenine group (animals received high-adenine diet for 4 weeks and saline for 12 weeks), and adenine + aliskiren group (animals received adenine for 4 weeks and aliskiren 10 mg/kg for 12 weeks). It was found that adenine caused significant decrease in body mass, Hb, HR, serum Ca(2+), eNOS and nrf2 expression, GSH, and catalase in kidney tissues with significant increase in arterial blood pressure (ABP), serum creatinine, BUN, plasma renin activity (PRA), K(+) and P, urinary albumin excretion (UAE), caspase-3, and MDA (lipid peroxidation marker) in kidney tissues compared to normal group (p < 0.05). Administration of aliskiren caused significant improvement in all studied parameters compared to adenine group (p < 0.05). We concluded that aliskiren has renoprotective effect against adenine-induced nephropathy. This might be due to inhibition of PRA, attenuation of oxidative stress, activation of Nrf2 and eNOS genes, and suppression of caspase-3.

Direct renin inhibitor therapy and swimming training: hemodynamic and cardiac effects in hypertensive and normotensive rats

Purpose: This study aimed to analyze the hemodynamic and cardiac effects of direct renin inhibitor (DRI) treatment and swimming training in hypertensive rats. Methods: Seventy-seven rats were divide into eight groups: sedentary normotensive (SN), trained normotensive (TN), sedentary normotensive treated with DRI (SN_DRI), trained normotensive treated with DRI (TN_DRI), sedentary hypertensive (SH), trained hypertensive (TH), sedentary hypertensive treated with DRI (SH_DRI), trained hypertensive treated with DRI (TH_DRI). Swimming training occurred for up to 60 min, five times a week for four weeks. The hypertensive animals were treated with 20 mg ċ kg−1 ċ day−1 L-NAME for four weeks. Groups treated with DRI received 10 mg ċ kg−1 ċ day−1 of aliskiren for four weeks. After the treatment period, all the animals underwent femoral artery catheterization surgery for direct measurement of cardiovascular variables. Results: The SH group presented hypertension (136.4 ± 5.0 mmHg) compared to the SN (107.1 ± 1.7 mmHg). The TH group showed lower mean arterial pressure (MAP) than the SH (121.1 ± 1.3 mmHg), but the treatment with DRI did not attenuate hypertension (128.2 ± 4.9 mmHg). The analysis of collagen areas demonstrated that treatment with DRI may attenuate cardiac remodeling in situations of hypertension, in the condition of treatment alone or combined with physical training. Conclusion: Both interventions in combination may be more effective at reducing cardiovascular risk in hypertensive subjects.

Effect of Direct Renin Inhibitor on Left Ventricular Remodeling in Patients With Primary Acute Myocardial Infarction

Some patients with acute myocardial infarction (AMI) have a poor prognosis due to left ventricular remodeling (LVR), resulting in the recurrence of congestive heart failure even when therapy with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) has been initiated. We investigated the effect of early administration of the direct renin inhibitor (DRI) aliskiren in combination with an ACEI or an ARB on LVR using cardiac magnetic resonance (CMR) imaging in patients with AMI.Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren 150 mg/day combined with an ACEI or an ARB (DRI group). CMR imaging was performed 7 days after AMI and 10 months later.CMR imaging revealed no significant changes in LV end-systolic volume, LV end-diastolic volume, or LV ejection fraction between the patients with and without DRI aliskiren. In the DRI group, plasma renin activity was significantly lower in both the acute and chronic phases; however, aldosterone levels were significantly lower in the acute but not the chronic phase.A low dose of aliskiren may be insufficient to maintain suppression of aldosterone under current standard therapies with an ACEI or an ARB and β-blocker in patients with primary AMI, and results in no attenuation of LVR.

Differential Effects of Aliskiren/Amlodipine Combination and High-Dose Amlodipine Monotherapy on Endothelial Function in Elderly Hypertensive Patients

The aim of this study was to compare the effects of direct renin inhibitor, aliskiren, and amlodipine combination therapy with those of high-dose amlodipine monotherapy on endothelial function in elderly hypertensive patients. Participants included 105 patients (mean age 77 years) who had receive 5mg amlodipine for 4 weeks. Patients were allocated to the aliskiren/amlodipine group (AL/AM) or the high-dose amlodipine (AM) group. The AL/AM group received 150mg aliskiren in addition to 5mg amlodipine for 8 weeks; then the dose of aliskiren was doubled to 300mg for another 8 weeks. The AM group received 10mg amlodipine for 16 weeks. Of the 105 patients, 87 who underwent measurements of brachial flow-mediated vasodilation (FMD) and nitroglycerin-mediated vasodilation (NMD) before and after the study were included in the analysis. Blood pressure-lowering effects were similar in the 2 groups. Plasma renin activity significantly decreased in the AL/AM group (P < 0.001) but increased in the AM group (P < 0.001). Improvement of FMD was found in the AL/AM group (2.6% to 3.7%, P = 0.001) but not in the AM group, while NMD did not change in either group. The changes in 24-hour systolic blood pressure (r = -0.60, P < 0.001) and diastolic blood pressure (r = -0.46, P = 0.004) were significantly correlated with improvement of FMD in the AL/AM group but not in the AM group. Addition of aliskiren improved endothelial function in elderly hypertensive patients treated with amlodipine. UMIN000010163.

GW24-e3848 The organ protective effect of direct renin inhibitor in a mouse model of type 2 diabetes

ObjectivesThe benefit of blocking the renin-angiotensin system (RAS) with conventional RAS blockers in cardiovascular diseases and nephropathy of patients with type 2 diabetes is now well established. Direct renin inhibitor...

The Effects of Direct Renin Inhibitor, Aliskiren, on Arterial Hypertension, Chronic Kidney Disease and Cardiovascular Disease: Optimal Pharmacotherapy

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of progression of arterial hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD). Previous studies suggested that a direct renin inhibitor, aliskiren, may be effective for blood pressure lowering, renoprotection and cardiovascular protection. This review focuses on the effects of aliskiren for arterial hypertension, CKD and CVD.

Direct renin inhibitor prevents and ameliorates insulin resistance, aortic endothelial dysfunction and vascular remodeling in fructose-fed hypertensive rats

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers can improve insulin resistance and vascular dysfunction in insulin-resistant rats; however, there are few reports on the effects of direct renin inhibitors on these conditions. We investigated the effects of a direct renin inhibitor, aliskiren, on insulin resistance, aortic endothelial dysfunction and vascular remodeling in fructose-fed hypertensive rats. Male Wistar-Kyoto rats were divided into four groups (n=6 per group) and studied for 8 weeks: Group Con: standard chow diet; group Fru: high-fructose diet (60% fructose); Group FruA: high-fructose diet with concurrent aliskiren treatment (100 mg kg(-1) per day); and Group FruB: high-fructose diet with subsequent aliskiren treatment 4 weeks later. Blood was collected for biochemical assays, and isolated rings of the thoracic aorta were obtained for analysis of vascular reactivity, vascular structure and lipid peroxide. Rats fed with high-fructose diets developed significant systolic hypertension, decreased plasma nitrite (NO(2); nitric oxide metabolite) levels and increased plasma glucose, insulin, triglyceride, total cholesterol and aortic lipid peroxide levels, and aortic wall thickness compared with control rats. Aliskiren treatment, either concurrent or subsequent, elevated plasma NO(2) levels and reduced systolic hypertension, insulin resistance, dyslipidemia, aortic lipid peroxide levels and aortic wall hypertrophy in FHR. The peak endothelium-dependent aortic relaxations were significantly higher in rats that received aliskiren treatment than in those that did not. In conclusion, our findings suggest that aliskiren prevents and ameliorates insulin resistance, aortic endothelial dysfunction and oxidative vascular remodeling in fructose-fed hypertensive rats.

Effect of Direct Renin Inhibitor, Aliskiren, on Peripheral Blood Monocyte Subsets and Myocardial Salvage in Patients With Primary Acute Myocardial Infarction

It remains unclear whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) have fully delivered the expected reduction in cardiovascular diseases. We investigated the effects of adding the direct renin inhibitor (DRI), aliskiren, to an ACEI or an ARB on monocyte subsets and myocardial salvage in patients with primary acute myocardial infarction (AMI). Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren combined with an ACEI or an ARB (DRI group). Two monocyte subsets (CD14(+)CD16(-) and CD14(+)CD16(+)) were measured by flow cytometry. The extent of myocardial salvage 7 days after AMI was evaluated by cardiac magnetic resonance imaging. Both plasma renin activity and aldosterone levels were significantly lower in the DRI group than in the non-DRI group. Peak levels of CD14(+)CD16(-) monocyte number and ratio were also significantly lower in the DRI group. The extent of myocardial salvage was significantly higher in the DRI group than in the non-DRI group (44.8 [41.2-53.1] vs. 36.0 [28.5-42.6], P=0.001). A DRI combined with an ACEI or an ARB can better improve the extent of myocardial salvage after AMI than an ACEI or an ARB alone in association with the decrease in circulating CD14(+)CD16(-) monocytes.

Abstract 8812: Direct Renin Inhibitor Ameliorates Insulin Resistance by Improving Insulin Signaling in the Skeletal Muscle in Experimental Post-Infarct Heart Failure

Background Insulin resistance has been shown to occur as a consequence of heart failure (HF). The activation of renin-angiotensin system may play an important role in this phenomenon. We thus investigated the effects of direct renin inhibitor, aliskiren, on the insulin resistance and the insulin signaling in the skeletal muscle from experimental HF after myocardial infarction (MI). Methods MI was created in male C57BL/6J mice by ligating the left coronary artery, and sham operation was also performed. Mice were divided into 4 groups; sham-operated (sham, n=10), sham treated with aliskiren (10mg/kg/day, n=10), MI (n=10), and MI treated with aliskiren (MI+Ali, n=10). After 4 weeks, echocardiographic and hemodynamic measurements were performed. Plasma glucose levels after intraperitoneal glucose or insulin load were measured. Proteins regulating insulin signaling were measured in the lower extremity skeletal muscle tissues by Western blot analysis. The lucigenin chemiluminescence elicited by •O 2 - and NAD(P)H oxidase activities were also measured in the skeletal muscle. Results Heart rate and aortic blood pressure were not affected by aliskiren in either group. MI mice showed left ventricular (LV) dilatation, dysfunction and an increase in LV end-diastolic pressure, which were not affected by aliskiren. Infarct size was comparable between MI and MI+Ali. Plasma glucose levels at baseline and after glucose load did not differ among groups. However, the decrease in plasma glucose after insulin load was smaller in MI than sham (14±5 vs. 36±2 %, p&lt;0.05), and was significantly ameliorated in MI+Ali (34±5 %, p&lt;0.05). Insulin-stimulated serine-phosphorylation of Akt and the translocation of glucose transporter-4 from cytosol to membrane were decreased in MI by 57 and 69 % of sham, respectively, Aliskiren significantly ameliorated them by 86 and 93 % of sham, respectively. Moreover, •O 2 - production and NAD(P)H oxidase activities were increased in MI and this increase was also inhibited in MI+Ali. Such effects of aliskiren were not observed in sham mice. Conclusions Aliskiren ameliorated insulin resistance associated with HF by improving insulin signaling, at least in part, via the inhibition of NAD(P)H oxidase-induced •O 2 - production in the skeletal muscle.

Direct Renin Inhibitor (Aliskiren) Improves Insulin Resistance and Impaired Insulin Signal in Post-Infarct Heart Failure

Objective: Insulin resistance has been shown to occur as a consequence of heart failure (HF). The activation of renin-angiotensin system may play an important role in this phenomenon. We thus investigated the effect of direct renin inhibitor, Aliskiren, on the insulin resistance after MI. Methods and Results: MI and sham operation were performed in male C57BL/6J mice. Mice were divided into 4 groups; sham-operated (sham, n=10), sham treated with Aliskiren (10mg/kg/day, n=7), MI (n=10), and MI treated with Aliskiren (MI+Aliskiren, n=9).