Aliskiren Reduces the Adrenal Zona Glomerulosa Apoptosis and Autophagy in Wistar Rats with 2K1C Hypertension (original) (raw)
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T he renin-angiotensin system is widely accepted as a central mediator of chronic kidney disease (CKD) and is the main target of therapies aiming to slow down or ameliorate the progression of the disease. 1 Aliskiren is a novel, direct inhibitor of renin activation that has been added to angiotensin-converting enzyme blockers and angiotensin II receptor 1 inhibitors and, at least theoretically, may avoid angiotensin II escape that is observed after treatment with drugs from the other 2 classes. Although the beneficial effect of aliskiren in normalizing blood pressure and proteinuria has been shown in both humans 4,5 and animal models, 6,7 data regarding its anti-inflammatory and, most importantly, its antifibrotic capacity in models of CKD are still missing. To evaluate the effect of aliskiren on regression of renal fibrosis, we used a heterozygous transgenic mouse model that expresses an artificial mouse renin gene (RenTg) in the liver at constantly high levels 8 against which alis...
The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor- and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 mol/L to 10 mol/L) did not inhibit binding of 125 I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor. (Hypertension. 2008;52:130-136.) Key Words: aliskiren Ⅲ renin inhibitor Ⅲ TG(mRen-2)rat Ⅲ diabetic nephropathy Ⅲ (pro)renin receptor
Pharmacological Reports, 2014
Background: Hypertensive nephropathy is moving up the charts to number 2 after diabetic nephropathy in terms of diagnostic frequency cited as causing end stage renal disease (ESRD). Method: Hypertensive nephropathy was produced in mildly hypertensive C57BL/6-(hREN)/(hAGT) double transgenic (dTG) mice with 20 mg/kg of cyclosporine A (CsA) administered subcutaneously (sc) daily for 28 days. CsA dose 20 mg/kg was selected for the study as this dose offered significant alteration in blood pressure, biochemical parameters and moderate nephropathy in kidney. Effect of aliskiren oral treatment twice daily consequently for 28 days at 10 mg/kg body weight was evaluated against CsA induced hypertensive nephropathy. Systolic blood pressure (SBP) was measured by non invasive tail cuff method. Kidney function test (blood urea nitrogen, serum creatinine, urea and uric acid) and kidney injury biomarker (tumor necrosis factor-alpha (TNF-a) and interlekin-6) level was assessed in serum, TNF-a, IL-6, transforming growth factor-beta1 (TGF-b1) and kidney injury molecule-1 (KIM-1) was assayed in kidney homogenate. Urinary KIM-1 levels were assessed as an early biomarker of nephropathy. Result: Significant hypertensive nephropathy and increase in serum levels of biomarkers was observed in CsA treated animals when compared with Control group. Aliskiren treatment elicited significant renoprotection by preventing the increase in blood pressure and levels of serum biomarkers and also reduced the nephropathic alterations in the kidney histoarchitecture. Conclusion: A correlation between pharmacological, biochemical and histological findings has been established in mouse model. The present findings have indicated the renoprotective activity of aliskiren in CsA induced hypertensive nephropathy, which may be due to its antihypertensive, anti-inflammatory as well as anti-apoptopic action.
Renin Inhibition by Aliskiren Prevents Atherosclerosis Progression
Hypertension, 2008
Hypertension is associated with increased risk of cardiovascular diseases. Antihypertensive treatment, particularly blockade of the renin-angiotensin system, contributes to prevent atherosclerosis-mediated cardiovascular events. Direct comparison of different antihypertensive treatments on atherosclerosis and particularly plaque stabilization is sparse. ApoE −/− mice with vulnerable (2-kidney, 1-clip renovascular hypertension model) or stable (1-kidney, 1-clip renovascular hypertension model) atherosclerotic plaques were used. Mice were treated with aliskiren (renin inhibitor), irbesartan (angiotensin-receptor blocker), atenolol (β-blocker), or amlodipine (calcium channel blocker). Atherosclerosis characteristics were assessed. Hemodynamic and hormonal parameters were measured. Aliskiren and irbesartan significantly prevented atherosclerosis progression in 2-kidney, 1-clip mice. Indeed, compared with untreated animals, plaques showed thinner fibrous cap ( P <0.05); smaller lipid ...
Brazilian Journal of Medical and Biological Research, 2015
Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK) and L-arginine treatment both alone and in combination on blood pressure (BP), and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C) hypertension, 2K1C+ +ALSK (ALSK), 2K1C+ +L-arginine (L-arg), and 2K1C+ +ALSK+ +L-arginine (ALSK+ +L-arg) treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+ +L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME) increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+ +L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+ +L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT 1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+ +L-arg groups, AT 2 expression increased in the ALSK+ +L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+ +L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+ +L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress.
Hypertension Management and End Organ Protection: Focus on Aliskiren
Clinical Medicine. Therapeutics
The renin-angiotensin system (RAS) activity is a key factor in the pathophysiology and development of hypertension, atherosclerosis, heart failure, and renal disease. It is unclear whether angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) have fully delivered the expected reductions in cardiovascular risk. In fact, the optimized RAS suppression is difficult to achieve with these agents, partly because ACE inhibitors and ARBs both activate compensatory feedback mechanisms that result in renin release and increase plasma renin activity (PRA). Molecular modeling was used to develop aliskiren, a potent, low-molecular-weight, nonpeptide, direct renin inhibitor with sufficient bioavailability to produce sustained suppression of PRA after oral administration. This report discusses the mechanisms of action of oral renin inhibitors and their pharmacokinetic properties. In addition, the report also evaluates the available data regarding the effects of the...
American journal of hypertension, 2011
The direct renin inhibitor aliskiren is known to exhibit a strong antihypertensive effect. However, the organoprotective potential of aliskiren beyond its antihypertensive properties is less clear. This study investigates the antifibrotic nephroprotective effects of aliskiren in a nonhypertensive mouse model for progressive renal fibrosis. COL4A3(-/-) mice received aliskiren via osmotic minipumps. Placebo-treated animals served as controls. Therapy was initiated in 6-week-old animals already showing renal damage (proteinuria ~1 g/l, starting renal fibrosis) and lasted for 4 weeks. Six animals were sacrificed after 9.5 weeks; serum urea and proteinuria were measured. Kidneys were further investigated using histological, immunohistological, and western blot techniques. Survival until end-stage renal failure was monitored in the remaining animals. COL4A3(-/-) mice did not develop hypertension. Aliskiren serum levels were in the therapeutic range (288 ± 44 ng/ml). Therapy significantly ...
Hypertension Research, 2012
Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, Po0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, Po0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.