Peripheral Levels of Renin-Angiotensin System Components Are Associated With Cognitive Performance in Huntington’s Disease

The renin-angiotensin system (RAS) has proven to be involved in the pathophysiology of neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), serving as a potential therapeutic target and a disease burden marker. Studies have associated negative clinical outcomes with the activation of the classical RAS arm composed of the angiotensin-converting enzyme (ACE) and angiotensin (Ang) II, while suggested positive outcomes with the activation of the counter-regulatory RAS arm involving ACE2 and Ang-(1–7). Huntington’s disease (HD) shares many pathological and clinical outcomes with AD and PD, but the evidence of direct involvement of RAS components in the pathophysiology of HD is still limited and needs further investigation. Herein, we investigated peripheral levels of the RAS components Ang II, Ang-(1–7), ACE, and ACE2 in controls, premanifest, and manifest HD gene carriers and their relationship with clinical outcomes. Peripheral blood samples were collected via phlebotomy, and plasma concentrations of RAS components were measured by Enzyme-Linked Immunosorbent Assay. Clinical evaluation included a questionnaire about socio-demographic characteristics, motor, and cognitive assessments. Results showed (1) no significant group differences in plasma concentrations of RAS components; (2) positive correlations between ACE2 and Verbal Fluency Test (VFT) scores; and (3) negative correlations between Ang II and Mini–Mental State Examination scores. These results corroborate the proposed balance between the classical (ACE/Ang II) and the counter-regulatory [ACE2/Ang-(1–7)] arms of the RAS, with the former associated with negative clinical outcomes and the latter with positive effects in HD.

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Mediation of humoral catecholamine secretion by the renin-angiotensin system in hypotensive rainbow trout (Oncorhynchus mykiss)

Journal of Endocrinology ◽

10.1677/joe.0.1600351 ◽

1999 ◽

Vol 160 (3) ◽

pp. 351-363 ◽

Cited By ~ 15

Author(s):

NJ Bernier ◽

H Kaiya ◽

Y Takei ◽

SF Perry

Keyword(s):

Blood Pressure ◽

Rainbow Trout ◽

Enzyme Inhibitor ◽

Plasma Concentrations ◽

Plasma Catecholamines ◽

Renin Angiotensin System ◽

Adrenergic System ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin

The individual contributions of, and potential interactions between, the renin-angiotensin system (RAS) and the humoral adrenergic stress response to blood pressure regulation were examined in rainbow trout. Intravenous injection of the smooth muscle relaxant, papaverine (10 mg/kg), elicited a transient decrease in dorsal aortic blood pressure (PDA) and systemic vascular resistance (RS), and significant increases in plasma angiotensin II (Ang II) and catecholamine concentrations. Blockade of alpha-adrenoceptors before papaverine treatment prevented PDA and RS recovery, had no effect on the increase in plasma catecholamines, and resulted in greater plasma Ang II concentrations. Administration of the angiotensin-converting enzyme inhibitor, lisinopril (10(-4) mol/kg), before papaverine treatment attenuated the increases in the plasma concentrations of Ang II, adrenaline, and noradrenaline by 90, 79, and 40%, respectively and also prevented PDA and RS recovery. By itself, lisinopril treatment caused a gradual and sustained decrease in PDA and RS, and reductions in basal plasma Ang II and adrenaline concentrations. Bolus injection of a catecholamine cocktail (4 nmol/kg noradrenaline plus 40 nmol/kg adrenaline) in the lisinopril+papaverine-treated trout, to supplement their circulating catecholamine concentrations and mimic those observed in fish treated only with papaverine, resulted in a temporary recovery in PDA and RS. These results indicate that the RAS and the acute humoral adrenergic response are both recruited during an acute hypotensive stress, and have important roles in the compensatory response to hypotension in rainbow trout. However, whereas the contribution of the RAS to PDA recovery is largely indirect and relies on an Ang II-mediated secretion of catecholamines, the contribution from the adrenergic system is direct and relies at least in part on plasma catecholamines.

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The Renin-Angiotensin System in Huntington’s Disease: Villain or Hero?

Protein and Peptide Letters ◽

10.2174/0929866527666200110154523 ◽

2020 ◽

Vol 27 (6) ◽

pp. 456-462 ◽

Cited By ~ 1

Author(s):

Thatiane C.G. Machado ◽

Cristina Guatimosim ◽

Lucas M. Kangussu

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Motor Impairment ◽

Renin Angiotensin System ◽

Peptide Hormone ◽

Angiotensin System ◽

Renin Angiotensin ◽

Hormone System

Huntington’s Disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by severe symptoms, including motor impairment, cognitive decline, and psychiatric alterations. Several systems, molecules, and mediators have been associated with the pathophysiology of HD. Among these, there is the Renin-Angiotensin System (RAS), a peptide hormone system that has been associated with the pathology of neuropsychiatric and neurodegenerative disorders. Important alterations in this system have been demonstrated in HD. However, the role of RAS components in HD is still unclear and needs further investigation. Nonetheless, modulation of the RAS components may represent a potential therapeutic strategy for the treatment of HD.

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A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00721.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. H968-H979 ◽

Cited By ~ 9

Author(s):

Neeru M. Sharma ◽

Shyam S. Nandi ◽

Hong Zheng ◽

Paras K. Mishra ◽

Kaushik P. Patel

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Paraventricular Nucleus ◽

Renin Angiotensin System ◽

Luciferase Reporter ◽

Mrna Levels ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin

An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3′-untranslated region (3′-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3′-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF. NEW & NOTEWORTHY Angiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.

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Downregulation of the renin-angiotensin system in streptozotocin-diabetic rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.262.1.e105 ◽

1992 ◽

Vol 262 (1) ◽

pp. E105-E109 ◽

Cited By ~ 9

Author(s):

L. A. Cassis

Keyword(s):

Adipose Tissue ◽

Replacement Therapy ◽

White Adipose Tissue ◽

Plasma Concentrations ◽

Renin Angiotensin System ◽

Diabetic Rats ◽

Angiotensin System ◽

Renin Angiotensin ◽

Brown Adipose ◽

Insulin Replacement

To determine if insulin has the ability to regulate components of the renin-angiotensin system, renin and angiotensinogen mRNA and plasma concentrations were determined in 4-wk streptozotocin (STZ)-diabetic rats. In another group of STZ-diabetic rats, replacement insulin therapy was given over the 4-wk period, and the above parameters were examined. In STZ-diabetic rats, there was a significant regression of white adipose tissue that was accompanied by an increase in the yield of RNA obtained. Changes in white adipose tissue were reversed by insulin replacement therapy in STZ-diabetic rats. There were no changes in brown adipose tissue weight or RNA yield in STZ-diabetic rats. Plasma renin activity (PRA) was significantly decreased in STZ-diabetic rats; however, plasma angiotensinogen concentration was not significantly affected by diabetes. PRA was restored to control levels in STZ-diabetic rats with insulin replacement. Kidney renin mRNA as well as liver, epididymal, and interscapular fat angiotensinogen mRNA were significantly decreased in STZ-diabetic rats. Renin and angiotensinogen mRNA were not significantly different from control in all tissues examined in STZ-diabetic rats with insulin replacement therapy. Results from this study suggest a downregulation of the renin-angiotensin system in 4-wk STZ-diabetic rats at the level of mRNA expression that is restored by replacement therapy with insulin; therefore, insulin may directly or indirectly regulate the renin-angiotensin system.

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Clinical outcomes in hypertensive patients treated with a single‐pill fixed‐dose combination of renin‐angiotensin system inhibitor and thiazide diuretic

Journal of Clinical Hypertension ◽

10.1111/jch.13413 ◽

2018 ◽

Vol 20 (12) ◽

pp. 1731-1738 ◽

Cited By ~ 3

Author(s):

Chien-Te Ho ◽

Ying‐Chang Tung ◽

Shing‐Hsien Chou ◽

Fu‐Chih Hsiao ◽

Yu‐Sheng Lin ◽

...

Keyword(s):

Clinical Outcomes ◽

Thiazide Diuretic ◽

Renin Angiotensin System ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Angiotensin System ◽

Hypertensive Patients ◽

Renin Angiotensin ◽

Single Pill ◽

Dose Combination

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The Biochemical Effects of Angiotensin-(1-7) on the Oxidative Stress Metabolism and Their Specific Parameters from the Temporal Lobe

Revista de Chimie ◽

10.37358/rc.20.6.8196 ◽

2020 ◽

Vol 71 (6) ◽

pp. 307-311

Author(s):

Sorin Ungurianu ◽

Constantin Trus ◽

Roxana-Rosmary Enciu

Keyword(s):

Oxidative Stress ◽

Temporal Lobe ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Angiotensin Peptides ◽

Vascular Area ◽

Ang Iv ◽

The One

It is already known from a variety of previous reports that an independent brain renin�angiotensin system (RAS) exists, completely separated from the one in the periphery. This independent brain RAS has all the precursors and the enzymatic structures necessary for the generation of the angiotensin peptides. Thus, in the last few years various groups started focusing on the more central effects of less known angiotensins (e.g in comparison with Angiotensin (Ang) II), namely Ang III, Ang IV, Ang-(1�7) or Ang 5-8. One of these newly emerging angiotensins which has become an increased center of interest in many studies is Ang-(1-7), which is a heptapeptide previously described especially for its opposite effects to Ang II, in the peripheral vascular area, but also described for some opposite central functions vs. Ang II. These aspects are completed with the fact that it was recently suggested that the renin�angiotensin system could modulate the oxidative stress metabolism, and also it seems that the manifestations of Angiotensin-(1-7) on the basal oxidative stress status are contradictory, with a variety of reports describing controversial (e.g. both pro-oxidant and antioxidant actions) effects for this heptapeptide. Our results presented here are confirming a possible antioxidant effect of Ang-(1�7) administration on rat, as shown by the increased levels of antioxidant enzymes from the temporal lobe (superoxide dismutase and glutathione peroxidase) and decreased levels of malondialdehyde, as an important lipid peroxidation parameter.

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Functional expression of the renin-angiotensin system in human podocytes

AJP Renal Physiology ◽

10.1152/ajprenal.00475.2004 ◽

2006 ◽

Vol 290 (3) ◽

pp. F710-F719 ◽

Cited By ~ 86

Author(s):

Max C. Liebau ◽

D. Lang ◽

J. Böhm ◽

N. Endlich ◽

Martin J. Bek ◽

...

Keyword(s):

Renin Angiotensin System ◽

Functional Expression ◽

Kidney Cortex ◽

Receptor Subtypes ◽

Ang Ii ◽

Angiotensin Receptor ◽

Angiotensin System ◽

Renin Angiotensin ◽

Beneficial Effects ◽

Glomerular Proteinuria

Experimental and clinical studies impressively demonstrate that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) significantly reduce proteinuria and retard progression of glomerular disease. The underlying intraglomerular mechanisms are not yet fully elucidated. As podocyte injury constitutes a critical step in the pathogenesis of glomerular proteinuria, beneficial effects of ACEI and ARB may partially result from interference with a local renin-angiotensin system (RAS) in podocytes. The knowledge of expression and function of a local RAS in podocytes is limited. In this study, we demonstrate functional expression of key components of the RAS in differentiated human podocytes: podocytes express mRNA for angiotensinogen, renin, ACE type 1, and the AT1 and AT2 angiotensin receptor subtypes. In Western blot experiments and immunostainings, expression of the AT1 and AT2 receptor was demonstrated both in differentiated human podocytes and in human kidney cortex. ANG II induced a concentration-dependent increase in cytosolic Ca2+ concentration via AT1 receptors in differentiated human podocytes, whereas it did not increase cAMP. Furthermore, ANG II secretion was detected, which was blocked by neither the ACEI captopril nor the renin inhibitor remikiren nor the chymase inhibitor chymostatin. ANG II secretion of podocytes was not increased by mechanical stress. Finally, ANG II was found to increase staurosporine-induced apoptosis in podocytes. We speculate that ACEI and ARB exert their beneficial effects, in part, by interfering with a local RAS in podocytes. Further experiments are required to identify the underlying molecular mechanism(s) of podocyte protection.

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Abstract 227: The Protective Effect of Kidney-Specific ACE Inhibition Against Chronic Angiotensin II Infusions is Associated with Blunted Intrarenal Renin-Angiotensin System Activation

Hypertension ◽

10.1161/hyp.60.suppl_1.a227 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Jorge F Giani ◽

Tea Djandjoulia ◽

Nicholas Fetcher ◽

Sebastien Fuchs ◽

Dale M Seth ◽

...

Keyword(s):

Renin Angiotensin System ◽

Fold Increase ◽

Ace Inhibition ◽

Sham Operation ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Intrarenal Ras ◽

Failed Induction

Introduction: The responses to chronic angiotensin (Ang) II infusions of gene-targeted mice lacking kidney angiotensin-converting enzyme (ACE), in terms of intrarenal Ang II accumulation, hypertension, sodium and water retention are all blunted or absent. The objective of this study was to determine if these reduced responses were associated with changes in the intrarenal renin-angiotensin system (RAS). METHODS: Mice lacking intrarenal ACE (ACE10/10) were generated by targeted homologous recombination placing the expression of ACE only in macrophages. As a result, these mice have normal circulating ACE levels, but no kidney ACE. Wild-type (WT) mice of the same background (C57Bl/J) served as controls. Mice were subjected to sham-operation or subcutaneous infusion of Ang II for two weeks (n=6-10, 400 ng/kg/min via osmotic minipump). Mean arterial pressure (MAP) was followed by telemetry. At the end of the experiment, the kidneys were collected for analysis. Ang II content was measured by RIA. Renal abundance of ACE, angiotensinogen (AGT) and Ang II receptor type 1 (AT1R) were determined by Western Blot in total kidney homogenates. Results: At baseline, the MAP of WT and ACE 10/10 mice was similar 110 ± 4 mmHg vs. 109 ± 3 mmHg respectively (p>0.05). However, when subjected to chronic Ang II infusions, the hypertensive response was blunted in ACE 10/10 mice (129 ± 6 mmHg) vs. WT (146 ± 5 mmHg; P<0.05). Also, intrarenal Ang II accumulation was lower in ACE10/10 mice (724 ± 81 fmol/g) vs. WT (1130 ± 105 fmol/g, p<0.05). In non-treated mice, intrarenal RAS components analysis revealed that the absence of ACE in ACE10/10 mice was accompanied by a significant reduction in AGT (0.41 ± 0.06) and increased AT1R expression (1.32 ± 0.05) when compared to WT (normalized to 1.00, p<0.05 in both instances). Importantly, after chronic Ang II infusions, AGT, ACE and AT1R expression increased in WT (1.36, 1.26 and 1.17 fold increase respectively compared to non-treated WT, p<0.05) but not in the ACE10/10 mice (1.19, 1.06, 0.89 fold increase respectively compared to non-treated ACE10/10, p>0.05). Conclusion: The blunted hypertension and Ang II accumulation of mice devoid of kidney ACE in response to Ang II infusions is associated with a failed induction of renal AGT and the AT1R.

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Activation of the Alternate Renin-Angiotensin System Correlates with the Clinical Status in Human Cirrhosis and Corrects Post Liver Transplantation

Journal of Clinical Medicine ◽

10.3390/jcm8040419 ◽

2019 ◽

Vol 8 (4) ◽

pp. 419 ◽

Cited By ~ 2

Author(s):

Stephen Casey ◽

Robert Schierwagen ◽

Kai Mak ◽

Sabine Klein ◽

Frank Uschner ◽

...

Keyword(s):

Liver Transplantation ◽

Liver Disease ◽

Animal Studies ◽

Clinical Status ◽

Renin Angiotensin System ◽

Blood Sampling ◽

Ang Ii ◽

Post Transplantation ◽

Angiotensin System ◽

Renin Angiotensin

Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.

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