Administration Of Aliskiren Research Articles

Cardiac and pulmonary expression of renin, prorenin, mast cells and macrophages in a rat model of fat embolism syndrome

Fat embolism induced in rats by intravenous injection of triolein(T) causes pulmonary inflammation, fibrosis, and vasculitis after 48 hours ort 10 weeks. Administration of Aliskiren, Captopril and Losartan drugs, which interfere with the renin angiotensin aldosterone system, ameliorates the pulmonary damage. Macrophages and mast cell number decreased with drugs administration. Hearts do not exhibit inflammation or vasculitis although significant emboli are detected at 48 hours. Pulmonary expression of renin, prorenin(R/P) positive cells are also increased after T injection. This study investigates whether the presence of R/P cells correlates with macrophages and mast cell invasion in the hearts and lungs.Methodology24 Sprague Dawley rats were divided into four groups and treated with 0.2 ml of T or Saline. Lungs and hearts from 3 animals from each group that were sacrificed 48 hours or 10 weeks, fixed in formalin and stained with Hematoxylin‐Eosin, Trichrome or immunostained with antibodies to CD117, CD68 to identify mast cells and macrophages. Sections of the heart and the lung were evaluated at 400X magnification. Cells were counted, histopathology examined and statistical significance evaluated using GraphPad software.ResultsWhile the lungs showed the previously reported, histopathological damage caused by the inflammation, vasculitis, fibrosis and cell necrosis, the hearts did not show such damage, thus confirming previous observations.Contrary to the lungs where the number of CD117, CD68 and R/P positive cells was significantly increased at both interval times, no difference in CD117, CD68, R/P positive cell numbers were observed in the heart. In the lungs, two distinct types of macrophages were identified, one large and the second one of normal size. Such histopathological changes were not observed in the hearts. Hearts exhibited distinct locations of CD117 and CD68 positive cells, with multiple cells located primarily near the myocardium and few in the adventitia of the coronary arteries, in contrast to lungs where the cells were mostly located around the arteries.ConclusionThe study confirms the previously reported histopathological difference of the T induced damage in the lungs compared to that of the hearts in this model of fat embolization. This finding highlights the variation in cellular response of diverse organs to fat embolism. This difference is not only related to the number of the inflammatory cells but also to their location in different organs as evidenced by the difference in the distribution and location of R/P cells in hearts and lungs. Future studies will investigate the underlying mechanisms that lead to pulmonary susceptibility while preserving cardiac integrity in response to a FE induced inflammatory response in order to better design a therapeutic intervention for the fat embolism syndrome.

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 ...

Aliskiren and Fenofibrate Constrict Liver Fibrosis by means of Focusing on TGF-β1/Smad Signaling Pathway and Actuating HGF Expression

Purpose: Liver fibrosis stems from changes in fibrotic genes expression in response to tissue damage in various chronic liver diseases, with no effective therapeutic program at present. This study designed to explore the possible protective effects and the molecular targets of aliskiren (ALS) and fenofibrate (FENO) against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Methods: Wister albino rats had been injected with 0.4ml/kg 50% CCl4, three times/week for eight weeks, to establish liver fibrosis model. Concurrently, ALS (25mg/kg/day) and/or FENO (25mg/kg/day) were orally administrated for 8 weeks to rats CCl4 intoxicated. Results: Treatment with ALS and/or FENO ameliorated oxidative stress and hepatocellular damage in CCl4-intoxicated rats as indicated by the marked reduction in hepatic lipid peroxidation and serum transaminases with concomitant significant increase in hepatic superoxide dismutase (SOD) as well as glutathione (GSH) content. The magnitude of liver inflammation and fibrosis was also alleviated by both medications, as is evident from the substantial decrease in hepatic proinflammatory and profibrotic cytokines such as tumor necrosis factor a (TNF-a), interlukin-6, (IL6), C-reactive protein (CRP) and transforming growth factor-β1 (TGF-β1) with restrain in fibrous deposition alongside architecture alteration that was shown upon histopathological examination. Additionally, simultaneous administration of ALS with FENO downregulated hepatic p-Smad3 protein and increased hepatic growth factor (HGF) expression in CCl4-intoxicated rats. Conclusion: Conclusively, this study highlights the hepatoprotective effect of ALS and FENO and imply that their anti-fibrotic mechanism involves blockade of TGF-β1/Smad signaling pathway, induction of HGF expression, besides modulation of inflammation as well as oxidative stress.

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.

Central Application of Aliskiren, a Renin Inhibitor, Improves Outcome After Experimental Stroke Independent of Its Blood Pressure Lowering Effect.

Epidemiological studies suggest that pharmacological reduction of systemic hypertension lowers incidence and severity of stroke. However, whether the reduction of blood pressure per se or the compounds used to reduce hypertension are responsible for this effect received little attention. In the current study we therefore aimed to investigate whether Aliskiren, a renin-inhibitor used to treat arterial hypertension, may improve outcome in a mouse model of ischemic stroke when applied centrally and in a dose not affecting blood pressure. Male C57BL/6 mice received 0.6, 2.0, or 6.0 μg Aliskiren or vehicle by intracerebroventricular injection as a pre-treatment and were then subjected to 60 min of middle cerebral artery occlusion (MCAo). Infarct volume, brain edema formation, mortality, antioxidant effects, and functional outcome were assessed up to seven days after MCAo. Central administration of Aliskiren (0.6 or 2.0 μg) had no effect on systemic blood pressure but significantly reduced infarct volume and brain edema formation, blunted mortality, and improved neurological outcome up to 1 week after MCAo. Due to the central and prophylactic administration of the compound, we cannot make any conclusions about the potency of Aliskiren for acute stroke treatment, however, our study clearly demonstrates, that in addition to lowering blood pressure Aliskiren seems to have a direct neuroprotective effect. Hence, renin-inhibitors may be an effective addition to prophylactic treatment regimens in stroke patients.

Juxtaglomerular Cell Tumor: Reviewing a Cryptic Cause of Surgically Correctable Hypertension

Juxtaglomerular cell tumor (JGCT), or reninoma, is a typically benign neoplasm generally affecting adolescents and young adults due to modified smooth muscle cells from the afferent arteriole of the juxtaglomerular apparatus. Patients experience symptoms related to hypertension and hypoka-lemia due to renin-secretion by the tumor. MRI, PET, CT, and renal vein catheterizations can be used to capture JGCTs, with laparoscopic ultrasonography being most cost-efec-tive. Surgical removal is the best option for management; electrolyte imbalances are a potential complication which may be assuaged via pre-surgical administration of aliskiren, a renin inhibitor. Considering the vast etiology for hypertension and rarity of JGCT, the diagnosing physician must have a high index of suspicion for JGCT. Early recognition and management can help prevent cardiovascular or pregnancy complications and fatalities, vascular invasion and metastasis, improve quality of life, and limit socioeconomic liabilities. Herein we review the epidemiology, genetics, histopathol-ogy, clinical presentation, and management of this rare condition. The impact of genetics on prognosis warrant further research.

Beneficial Changes Promoted by L‐arginine and Aliskiren in Resistance Vessels in 2K1C hypertensive rats

Renovascular hypertension is characterized by increased angiotensin II and oxidative stress and by endothelial dysfunction. By acting on multiple targets and promoting diverse actions, angiotensin II (Ang II) plays a pivotal role in vascular dysfunction. The purpose of this study was to test whether the administration of aliskiren (ALSK) and L‐arginine (L‐arg) would restore endothelial dysfunction and reduce inflammation and oxidative stress in a rat renovascular hypertension model. Hypertension was induced by clipping the right renal artery, and the following five groups were divided: SHAM operated; 2‐kidney, 1‐clip (2K1C); 2K1C plus ALSK; 2K1C plus L‐ARG; and 2K1C plus ALSK+ L‐ARG. The vascular reactivity to norepinephrine (NE; 10(−9) to 2 × 10(−3) mol/L) and acetylcholine (ACh; 10(−10) to 10(−3) mol/L) was evaluated in the mesenteric arteriolar bed through concentration‐effect curves. The structure was assessed by histology and biomolecular analyzes were done via western blot, lipid peroxidation, DHE and DAF. For 4 weeks, blood pressure (BP) was monitored and endothelium‐dependent vasoconstriction and relaxation were assessed in mesenteric arteriolar. ALSK+L‐arg reduced BP and the contractile response to norepinephrine and improved acetylcholine relaxation. Incubation with N‐nitro‐L‐arginine methyl ester (L‐NAME) and L‐NAME+ Indometacin increased the response to norepinephrine in the 2K1C group and the effect was greater and partially improved, respectively, with the treatments. However, It was improved acetylcholine relaxation with the both of the treatments. The bioavailability of nitric oxide increased with the treatments, and the inflammation and oxidative stress was reduced with the treatments. L‐arginine and aliskiren attenuates the morphofunctional deleterious effects of Ang II on resistance vessels. The benefits of L‐arginine and aliskiren seem to occur through restoring the balance of ROS/NO. Therefore, this study opened new avenues for further clinical targeting of the treatment of cardiovascular diseases related to activation of the renin‐angiotensin system. In conclusion, combined ALSK+L‐arg treatment normalizes BP and prevents endothelial dysfunction in 2K1C hypertensive rats.Support or Funding InformationThis research was supported by a CNPq research grants. This study was funded by Fundação de Amparo a Pesquisa do Espirito Santo (FAPES‐Brazil) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq‐Brazil).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Role of renin-angiotensin system antagonists in the prevention of bevacizumab- and sunitinib-mediated cardiac dysfunction.

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg-1·wk-1), or 3) SNT (40 mg·kg-1·day-1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

MINIMAL EFFECT OF ALISKIREN ON MAST CELLS COUNT AND RENAL VASCULAR DAMAGE IN ACUTE RAT MODEL OF TRIOLEIN INDUCED PULMONARY FAT EMBOLISM.

IntroductionIn a rat model of fat embolism (FE) induced by injection of triolein (T) a severe inflammatory reaction leads to vasoconstriction and pulmonary fibrosis (1). Mast cell numbers are significantly increased in the lungs of the treated animals (2), and mast cell inhibition improves pulmonary vascular remodeling in pulmonary hypertension (3).There is evidence that the renin angiotensin system (RAS) is involved since drugs related to this system: captopril, losartan and aliskiren, prevent the pulmonary vasculitis and fibrosis in the early phase (48 hours) (4,5). However, aliskiren (ALI), a direct renin inhibitor, had a minimal effect on renal vasculitis, and fibrotic changes (6). In this study we evaluated the effect of T and ALI on renal mast cells.Materials and methods22 Sprague Dawley rates (250–300g BW) received T (0.2 ml n=18) or saline n=4. The T treated rats, divided into 3 groups of 6 each, were IP injected one hour later either with 0.2 ml saline, ALI 50 mg/kg or AL I 100 mg/kg. Four controls received saline.48 hours later rats were killed under isoflurane anesthesia and the kidneys and lungs stained with H&E, Trichrome, SMA1 for inflammation and fibrosis, and CD117 for mast cells. 10 photographs at 200× were taken for slides of each organ by two pathologists unaware of the slides' identity, mast cells were counted and pathological damage evaluated.ResultsRenal fibrosis and vasculitis were irrelevant by observation with all SM1, Trichrome or H&E stains, with the exception of the media adventitia ratio (MAR) of arteries (p= 0.007) which significantly increased after T‐saline treatment but not after ALI administration. These findings are in contrast with the observations of the lungs where the damage was severe and reduced by both ALI doses. Kidneys of ALI 100 mg/kg treated rats were similar to those ones of T+Saline or of the controls. Although a mild mast cell increase was noted in kidneys of T+Saline treated animals, no statistically significant difference in mast cells was observed.ConclusionRenal findings were quite different from our lung findings in either histopathological damage or mast cell accumulation. The study suggests that the RAS system influence on the kidneys differs from that of the lung at this acute stage of fat embolism.Support or Funding InformationSupported by the Catherine T Geldmacher Foundation, St. Louis, MOThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Inhibition of Aneurysm Progression by Direct Renin Inhibition in a Rabbit Model

Angiotensin II is thought to participate in aneurysm formation, because of its ability to induce and perpetuate inflammation in the aortic wall. Because activation of renin is the first step of the renin-angiotensin system, renin inhibition could inhibit all components of this system effectively. Therefore, we examined the hypothesis that direct inhibition of renin activity could decrease the expansion of aortic aneurysm using a rabbit model. Aortic dilatation was induced by incubation with elastase around the rabbit abdominal aorta. Continuous administration of a direct renin inhibitor, aliskiren, was started at 1 week before incubation with elastase and continued for 5 weeks. Treatment with aliskiren markedly inhibited tissue renin activation and resulted in a significant reduction in angiotensin I and II production in the aneurysm wall. Consequently, the inhibition of renin activity prevented the expansion of experimental aortic aneurysm associated with preservation of the medial layer, independent of its blood pressure-lowering effect. Administration of aliskiren led to the inhibition of activation of NF-κB (nuclear factor-κB), AP-1 (activator protein-1), and CREB (cAMP response element-binding protein), which are thought to cooperatively regulate the inflammatory gene expression profile associated with aneurysm formation. As a result, treatment with aliskiren inhibited macrophage accumulation through suppression of MCP-1 (monocyte chemoattractant protein-1) and CCL4 (C-C motif chemokine ligand 4) expression, and TNF-α (tumor necrosis factor-α) production and activation of MMP-2 (matrix metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9) were also suppressed in the aneurysm wall. In addition, inhibition of (pro)renin receptor elevation was also observed after treatment with aliskiren. Direct inhibition of renin activity using aliskiren prevented the progression of aortic aneurysm, suggesting it as a therapeutic option to treat abdominal aortic aneurysm.

Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats.

Renin–angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar–Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats.

Abstract 253: The Direct Renin Inhibitor Aliskiren Prevents Endothelial Dysfunction in Spontaneously Hypertensive Rat Aortas

Introduction: Hypertension is a significant medical problem. Aliskiren is a novel anti-hypertensive agent that inhibits renin directly. We tested the hypothesis that aliskiren prevents endothelial dysfunction in spontaneously hypertensive rats (SHRs). Methods: SHRs and age-matched Wistar Kyoto (WKY) rats were randomly divided and subjected to oral administration of aliskiren (10 mg/kg/day) or vehicle for 8 weeks. Blood pressure was monitored bi-weekly by a tail-cuff method. After an initial equilibration period, each ring was contracted by elevated KCl (60 mmol/L) to ensure a level of contractility suitable for subsequent experimentation. To examine endothelium-dependent relaxations in phenylephrine-contracted rings, two consecutive concentration-response curves to acetylcholine (ACh; 3 nmol/L -30 μmol/L) were constructed. In some phenylephrine-contracted rings without intact endothelium, sodium nitroprusside (SNP; 3 nmol/L – 10μmol/L) were applied cumulatively to the bathing solution to test the sensitivity of vascular smooth muscle cells (VSMCs) to NO. Results: Aliskiren reduced systolic blood pressure (SBP) to 155.6 ± 1.87 mmHg as compared to 165.3 ± 3.2 mmHg in vehicle-treated SHRs (n = 7), while chronic aliskiren administration did not affect SBP in WKY rats. SHR aortas with endothelium relaxed less in response to different concentrations of ACh than age-matched WKY rat aortas and ACh failed to cause relaxations of aortic rings without endothelium. By contrast, endothelium-independent relaxations caused by sodium nitroprusside (SNP) were comparable in aortas from SHR and WKY rats. Chronic aliskiren administration improved endothelium-dependent dilatations of aortas from SHRs compared to vehicle-treated SHRs, but this was unaffected in WKY rats. Endothelium-independent relaxations to SNP were not significantly different in aortas from the four treatment groups. Conclusions: Aliksiren reduces blood pressure and improves endothelium-dependent dilatations of SHRs. Figure 1. Effects of 8-week treatment of aliskiren on acetylcholine (ACh)-induced endothelium-dependent dilatations in SHR (A) and WKY (B) aortas. Results are mean ± SEM of 7 experiments. *p<0.05.

The renin inhibitor aliskiren protects rat lungs from the histopathologic effects of fat embolism.

Fat embolism (FE) and the consequent FE syndrome occurring after trauma or surgery can lead to serious pulmonary injury, including ARDS and death. Current treatment of FE syndrome is limited to supportive therapy. We have shown in a rat model that the renin angiotensin system plays a significant role in the pathophysiology of FE because drugs interfering with the renin angiotensin system, captopril and losartan reduce the histopathologic pulmonary damage. The purpose of the current study was to determine if inhibition of renin by aliskiren, an FDA-approved drug for treating hypertension, would produce effective protection in the same model. The FE model used intravenous injection of the neutral fat triolein in unanesthetized rats. Intraperitoneal injections of saline or aliskiren at either 50 or 100 mg/kg were performed 1 hour after FE induction via triolein. Rats were euthanized at 48 hours, and various histologic stains were used to examine the lungs. (1) Fibrosis: rats treated with triolein showed significant fibrotic changes with increased collagen and myofibroblast activation (p < 0.0001 for both trichrome and α-smooth muscle actin staining). Aliskiren blocked this inflammatory and profibrotic process to a level indistinguishable from the controls (p < 0.0001 for both trichrome and α-smooth muscle actin staining). (2) Fat: rats treated with triolein showed a statistically significant increase in fat (p = 0.0006). Subsequent aliskiren administration at both doses reduced the size, distribution, and amount of fat droplets (low dose, p = 0.0095; high dose, p = 0.0028). (3) Vessel patency: the low dose of aliskiren blocked the reduction of lumen patency observed after triolein administration (p = 0.0058). Aliskiren protected the lungs of rats from gross and histopathologic FE-induced pulmonary damage at 48 hours. Clinical implications include the use of aliskiren both prophylactically (before certain orthopedic procedures) and therapeutically (after severe trauma) to prevent the consequent severe pulmonary pathologic sequelae.

Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension.

The renin-angiotensin system (RAS) in the brain is a critical determinant of blood pressure, but the mechanisms regulating RAS activity in the brain remain unclear. Expression of brain renin (renin-b) occurs from an alternative promoter-first exon. The predicted translation product is a nonsecreted enzymatically active renin whose function is unknown. We generated a unique mouse model by selectively ablating the brain-specific isoform of renin (renin-b) while preserving the expression and function of the classical isoform expressed in the kidney (renin-a). Preservation of renal renin was confirmed by measurements of renin gene expression and immunohistochemistry. Surprisingly, renin-b-deficient mice exhibited hypertension, increased sympathetic nerve activity to the kidney and heart, and impaired baroreflex sensitivity. Whereas these mice displayed decreased circulating RAS activity, there was a paradoxical increase in brain RAS activity. Physiologically, renin-b-deficient mice exhibited an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. At the molecular level, renin-b-deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus, which correlated with an increased renal sympathetic nerve response to leptin, which was dependent on angiotensin-II type 1 receptor activity. Interestingly, despite an ablation of renin-b expression, expression of renin-a was significantly increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of RAS activity in the brain by a coordinated regulation of the renin isoforms, with expression of renin-b tonically inhibiting expression of renin-a under baseline conditions. Impairment of this control mechanism causes neurogenic hypertension.

Aliskiren targets multiple systems to alleviate cancer cachexia.

To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10mg/kg body weight(BW)] on day5 (as a preventive strategy, AP group) or on day12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system(RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome aswellas ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway(ALP) and ubiquitin-proteasome pathway(UPP).

Aliskiren Administration during Early Postnatal Life Sex-Specifically Alleviates Hypertension Programmed by Maternal High Fructose Consumption.

Key points summary Maternal high-fructose (HF) induces programmed hypertension in adult offspring.Early aliskiren administration prevents HF-induced hypertension in both sexes of adult offspring.HF regulates RAS components in the offspring kidney in a sex-specific manner.HF alters renal transcriptome, with female offspring being more sensitive.Deprogramming strategy to prevent hypertension might be sex-specific.Background: Maternal high fructose (HF) intake induced renal programming and hypertension in male adult offspring. We examined whether maternal HF intake causes programmed hypertension and whether aliskiren administration confers protection against the process in a sex-specific manner, with a focus on the transcriptome changes in the kidney using next-generation RNA sequencing (NGS) technology and renin-angiotensin system (RAS).Methods: Pregnant Sprague—Dawley rats received regular chow or chow supplemented with 60% fructose throughout pregnancy and lactation. Offspring were assigned to six groups: male control, male HF (MHF), MHF+Aliskiren, female control, female HF (FHF), and FHF+Aliskiren. Oral aliskiren 10 mg/kg/day was administered via gastric gavage between 2 and 4 weeks of age. Rats were sacrificed at 12 weeks of age.Results: Maternal HF intake induced programmed hypertension in 12-week-old offspring of both sexes. HF regulated renal transcriptome and RAS components in the offspring kidney in a sex-specific manner. Aliskiren administration prevented HF-induced programmed hypertension in both sexes of adult offspring. Aliskiren administration increased ACE2 and MAS protein levels in female kidneys exposed to maternal HF intake.Conclusion: Maternal HF induced programmed hypertension in both sexes of adult offspring, which was sex-specifically mitigated by early aliskiren administration. Better understanding of the sex-dependent mechanisms that underlie maternal HF-induced renal programming will help develop a novel sex-specific strategy to prevent programmed hypertension.

Aliskiren and l-arginine treatments restore depressed baroreflex sensitivity and decrease oxidative stress in renovascular hypertension rats.

Renovascular hypertension is characterized by increased angiotensin II and oxidative stress, and by endothelial dysfunction. The purpose of this study was to test whether the administration of aliskiren (ALSK) and l-arginine (l-ARG) would restore impaired baroreflex sensitivity and reduce oxidative stress in a rat renovascular hypertension model. Hypertension was induced by clipping the left renal artery, and the following five groups were created: SHAM; two-kidney, 1-clip (2K1C); 2K1C plus ALSK (ALSK); 2K1C plus l-ARG (l-ARG); and 2K1C plus ALSK+l-ARG (ALSK+l-ARG). After 21 days of treatment, only the ALSK+l-ARG group was effective in normalizing the arterial pressure (108.8±2.8 mm Hg). The l-ARG and ALSK+l-ARG groups did not show hypertrophy of the left ventricle. All the treatments restored the depressed baroreflex sensitivity to values found in the SHAM group. Acute administration of TEMPOL restored the depressed baroreflex sensitivity in the 2K1C group to values that resembled those presented by the other groups. All treatments were effective for an increase in the antioxidant pathway and reduction in the oxidative pathway. In conclusion, the treatment with ALSK or l-ARG reduced oxidative stress and restored reduced baroreflex sensitivity in renovascular hypertension. In addition, the treatments were able to normalize blood pressure and reverse left ventricular hypertrophy when used in combination.

Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

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.

Angiotensinogen Exerts Effects Independent of Angiotensin II.

This study determined whether angiotensinogen (AGT) has angiotensin II-independent effects using multiple genetic and pharmacological manipulations. All study mice were in low-density lipoprotein receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were >90% lower compared with their wild-type littermates. HypoAGT mice had lower systolic blood pressure, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in low-density lipoprotein receptor -/- mice. In mice with established adiposity, administration of AGT antisense oligonucleotide versus aliskiren led to equivalent reductions of systolic blood pressure and atherosclerosis. AGT antisense oligonucleotide administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat, and human revealed 4 highly conserved sequences within the des(angiotensin I)AGT domain. des(angiotensin I)AGT, through adeno-associated viral infection in hepatocyte-specific AGT-deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis. AGT contributes to body weight gain and liver steatosis through functions of the des(angiotensin I)AGT domain, which are independent of angiotensin II production.