Comparative assessment of CacyBP/SIP, ß-catenin and cannabinoid receptors in the adrenals of hypertensive rats.

Taking into account homeostatic disorders resulting from arterial hypertension and the key importance of CacyBP/SIP, ß-catenin and endocannabinoids in the functioning of many organs, it was decided to assess the presence and distribution of CacyBP/SIP, ß-catenin, CB1 and CB2 in the adrenal glands of hypertensive rats of various aetiology. The study was conducted on the adrenal glands of rats with spontaneous and renovascular hypertension. The expression of CacyBP/SIP, ß-catenin, CB1 and CB2 was detected by immunohistochemistry and real-time PCR method. The results of the present study revealed both lower gene expression and immunoreactivity of CacyBP/SIP in the adrenal glands of all hypertensive groups compared to the normotensive rats. This study demonstrated a reduction in the immunoreactivity and expression of the ß-catenin, CB1 and CB2 genes in the adrenals of 2K1C rats. While in SHR, the reaction showing ß-catenin and CB1 was very weak or negative, and the expression of CB2 in the adrenal glands of these rats increased. The results of this study show, for the first time, marked differences in the expression of CacyBP/SIP, ß-catenin and CB1 and CB2 cannabinoid receptors in the adrenal glands of rats with primary (SHR) and secondary hypertension (2K1C).

Apelin-13: a novel approach to suppressing renin production in RVHT.

Renovascular hypertension (RVHT) is characterized by renal artery stenosis and overactivated renin-angiotensin system (RAS). Apelin, known for its negative modulation of RAS, has protective effects against cardiovascular diseases. The role and mechanisms of the primary active form of apelin, apelin-13, in RVHT are unclear. In this study, male Sprague-Dawley rats were divided into control, two-kidney one-clip (2K1C) model, and 2K1C with apelin-13 treatment groups. Renin expression was analyzed using immunohistochemistry and molecular techniques. Full-length (pro)renin receptor (fPRR) and soluble PRR (sPRR) levels were assessed via Western blotting, and cAMP levels were measured using ELISA. Plasma renin content, plasma renin activity (PRA), angiotensin II (ANG II), and sPRR levels were determined by ELISA. Human Calu-6 and mouse As4.1 cells were used to investigate renin production mechanisms. The 2K1C model exhibited increased systolic blood pressure, plasma renin content, PRA, sPRR, and ANG II levels, while apelin-13 treatment reduced these elevations. Apelin-13 inhibited cAMP production, renin mRNA expression, protein synthesis, and PRR/sPRR protein expression in renal tissue. In Calu-6 cells, cAMP-induced fPRR and site-1 protease (S1P)-derived sPRR expression, which was blocked by cAMP-responsive element-binding protein (CREB) inhibition. Apelin-13 suppressed cAMP elevation, CREB phosphorylation, fPRR/sPRR protein expression, and renin production. Recombinant sPRR (sPRR-His) stimulated renin production, which was inhibited by the PRR decoy peptide PRO20 and S1P inhibitor PF429242. These findings suggest that apelin-13 inhibits plasma renin expression through the cAMP/PKA/sPRR pathway, providing a potential therapeutic approach for RVHT. Understanding the regulation of renin production is crucial for developing effective treatments.NEW & NOTEWORTHY Our research elucidated that apelin-13 inhibits renin production through the cAMP/PKA/soluble (pro)renin receptor pathway, presenting a promising therapeutic approach for renovascular hypertension (RVHT) by targeting renin expression mechanisms. These findings underscore the potential of apelin-13 as a novel strategy to address RVHT.

Renal Autotransplantation for Uncontrolled Hypertension in Nonatherosclerotic Renal Artery Stenosis-2 Case Reports and a Brief Review of the Literature.

Fibromuscular dysplasia is the most common cause of renovascular hypertension in young adults under 40 years old. It is potentially amenable to renal artery angioplasty, which frequently normalizes blood pressure. However, limited options exist if angioplasty is not technically possible, or restenosis occurs. Here, we describe 2 patients who presented with hypertension secondary to renal artery stenosis. In the first case, a young adult with hypertension secondary to renal artery stenosis (fibromuscular dysplasia), developed restenosis 11 weeks after an initially successful renal artery angioplasty. In the second case, a patient with neurofibromatosis type 1 was diagnosed with hypertension secondary to renal artery stenosis. Angioplasty was not possible due to multiple branch occlusions. Both individuals went on to have successful renal autotransplantations, which ultimately cured their hypertension. In this article, we review the background, indications, and blood pressure outcomes in relation to renal autotransplantation in nonatherosclerotic renal artery stenosis.

Montelukast Ameliorates 2K1C-Hypertension Induced Endothelial Dysfunction and Associated Vascular Dementia.

BACKGROUND: Declined kidney function associated with hypertension is a danger for cognitive deficits, dementia, and brain injury. Cognitive decline and vascular dementia (VaD) are serious public health concerns, which highlights the urgent need for study on the risk factors for cognitive decline. Cysteinyl leukotriene (CysLT1) receptors are concerned with regulating cognition, motivation, inflammatory processes, and neurogenesis. OBJECTIVE: This research aims to examine the consequence of montelukast (specific CysLT1 antagonist) in renovascular hypertension 2-kidney-1-clip-2K1C model-triggered VaD in experimental animals. METHODS: 2K1C tactics were made to prompt renovascular hypertension in mature male rats. Morris water maze was employed to measure cognition. Mean arterial pressure (MAP), serum nitrite levels, aortic superoxide content, vascular endothelial activity, brain's oxidative stress (diminished glutathione, raised lipid peroxides), inflammatory markers (IL-10, IL-6, TNF-α), cholinergic activity (raised acetylcholinesterase), and cerebral injury (staining of 2, 3, 5- triphenylterazolium chloride) were also examined. RESULTS: Montelukast in doses of 5.0 and 10.0 mg kg-1 was used intraperitoneally as the treatment drug. Along with cognitive deficits, 2K1C-operated rats showed elevated MAP, endothelial dysfunction, brain oxidative stress, inflammation, and cerebral damage with diminished serum nitrite/nitrate. Montelukast therapy significantly and dose-dependently mitigated the 2K1Chypertension- provoked impaired behaviors, biochemistry, endothelial functions, and cerebral infarction. CONCLUSION: The 2K1C tactic caused renovascular hypertension and associated VaD, which was mitigated via targeted regulation of CysLT1 receptors by montelukast administration. Therefore, montelukast may be taken into consideration for the evaluation of its complete potential in renovascular-hypertension-induced VaD.

A Rare Case of Focal Renal Fibromuscular Dysplasia Treated With Angioplasty: A Case Report.

BACKGROUND: Fibromuscular dysplasia is an idiopathic, segmental, nonatherosclerotic, noninflammatory vascular disease that can lead to arterial stenosis, tortuosity, occlusion, aneurysms, and dissection. Fibromuscular dysplasia is a rare cause of hypertension that can easily be missed. To date, there has been no definitive treatment for fibromuscular dysplasia. CASE REPORT: In this report, we present an uncommon case of renovascular hypertension in a 21-year-old non-white female with a 3-year history of hypertension secondary to fibromuscular dysplasia involving bilateral renal arteries. Computed tomography angiography during the arterial phase revealed distal focal narrowing of the right main renal artery, distal focal narrowing of the left main renal artery, and proximal focal narrowing of the left accessory lower renal artery. Percutaneous balloon dilatation of the stenotic lesion was performed successfully up to 1 year After the procedure, the arterial blood pressure was within the normal range (110/70 to 125/75 mmHg) without medication. After 1 year of follow-up, CTA revealed re-stenosis in left main renal artery without clinical symptoms and normal blood pressure. Repeated procedure was done successfully. CONCLUSIONS: This case report highlights the difficulty in the diagnosis and treatment of focal fibromuscular dysplasia in young non-white female patients. Computerized tomographic angiography is a useful tool for identifying the cause and showing the benefit of percutaneous transluminal renal angioplasty treatment for this rare entity, as an early percutaneous angioplasty intervention may have a clinical cure for hypertension.

Cardiovascular outcomes improve in children with renovascular hypertension following endovascular and surgical interventions.

BACKGROUND: Renovascular hypertension (RenoVH) is a cause of hypertension in children. A common cause of RenoVH is renal artery stenosis which acts by reducing blood supply to renal parenchyma and activating the renin-angiotensin-aldosterone axis, often leading to cardiac remodelling. This longitudinal observational study aims to describe occurrence of cardiovascular changes secondary to RenoVH and also any improvement in cardiac remodelling after successful endovascular and/or surgical intervention. METHODS: All patients with RenoVH referred to our centre, who received ≥ 1 endovascular intervention (some had also undergone surgical interventions) were included. Data were collected by retrospective database review over a 22-year period. We assessed oscillometric blood pressure and eight echocardiographic parameters pre- and post-intervention. RESULTS: One hundred fifty-two patients met inclusion criteria and had on average two endovascular interventions; of these children, six presented in heart failure. Blood pressure (BP) control was achieved by 54.4% of patients post-intervention. Average z-scores improved in interventricular septal thickness in diastole (IVSD), posterior Wall thickness in diastole (PWD) and fractional shortening (FS); left ventricular mass index (LVMI) and relative wall thickness (RWT) also improved. PWD saw the greatest reduction in mean difference in children with abnormal (z-score reduction 0.25, p < 0.001) and severely abnormal (z-score reduction 0.23, p < 0.001) z-scores between pre- and post-intervention echocardiograms. Almost half (45.9%) had reduction in prescribed antihypertensive medications, and 21.3% could discontinue all antihypertensive therapy. CONCLUSIONS: Our study reports improvement in cardiac outcomes after endovascular + / - surgical interventions. This is evidenced by BP control, and echocardiogram changes in which almost half achieved normalisation in systolic BP readings and reduction in the number of children with abnormal echocardiographic parameters. A higher resolution version of the Graphical abstract is available as Supplementary information.

Kidney Intrinsic Mechanisms as Novel Targets in Renovascular Hypertension.

Almost a hundred years have passed since obstruction of the renal artery has been recognized to raise blood pressure. By now chronic renovascular disease (RVD) due to renal artery stenosis is recognized as a major source of renovascular hypertension and renal disease. In some patients, RVD unaccompanied by noteworthy renal dysfunction or blood pressure elevation may be incidentally identified during peripheral angiography. Nevertheless, in others, RVD might present as a progressive disease associated with diffuse atherosclerosis, leading to loss of renal function, renovascular hypertension, hemodynamic compromise, and a magnified risk for cardiovascular morbidity and mortality. Atherosclerotic RVD leads to renal atrophy, inflammation, and hypoxia but represents a potentially treatable cause of chronic renal failure because until severe fibrosis sets in the ischemic kidney, it retains a robust potential for vascular and tubular regeneration. This remarkable recovery capacity of the kidney begs for early diagnosis and treatment. However, accumulating evidence from both animal studies and randomized clinical trials has convincingly established the inadequate efficacy of renal artery revascularization to fully restore renal function or blood pressure control and has illuminated the potential of therapies targeted to the ischemic renal parenchyma to instigate renal regeneration. Some of the injurious mechanisms identified as potential therapeutic targets included oxidative stress, microvascular disease, inflammation, mitochondrial injury, and cellular senescence. This review recapitulates the intrinsic mechanisms that orchestrate renal damage and recovery in RVD and can be harnessed to introduce remedial opportunities.

Chronic red laser treatment induces hypotensive effect in two-kidney one-clip model of renovascular hypertension in rat.

To evaluate whether the chronic effect of photobiomodulation therapy (PBM) on systolic arterial pressure (SAP) from two kidneys one clip (2 K-1C) hypertension animal models can cause a hypotensive effect. Serum levels of nitric oxide were also analyzed and the assessment of lipid peroxidation of the thoracic aorta artery. Male Wistar rats were used. Hypertensive animals (2 K-1C) with Systolic arterial pressure (SAP) greater than or equal to 160 mmHg were used. Systolic arterial pressure (SAP) was determined by the tail plethysmography technique. Normotensive (2 K) and hypertensive (2 K-1C) rats were treated to PBM for 4 weeks using a laser whose irradiation parameters were: red wavelength (λ) = 660 nm: operating continuously; 56 s per point (3 points) spot size = 0.0295 cm2; average optical power of 100 mW; energy of 5.6 J per point; irradiance of 3.40 W/cm2; fluency of 190 J/cm2 per point. The application was on the animals tails, at 3 different points simultaneously, in contact with the skin. To assess serum nitrite and nitrate (NOx) levels, blood collection was performed after chronic PBM treatment, 24 h after the last laser application. The evaluation of the lipid peroxidation of the thoracic aorta artery was performed by measuring the concentration of hydroperoxide by the FOX method. Chronic photobiomodulation therapy (PBM) by red laser (660 nm) can induce a hypotensive effect in 64% of 2 K-1C hypertensive animals, which we say responsive animals. There was no difference in serum NO levels 24 h after the last red laser application, between treated and non-treated groups. Aortic rings from 2 K-1C hypertensive animals present a higher lipid peroxidation. The chronic PBM treatment by red laser decreased aortic rings lipid peroxidation in hypertensive responsive groups, compared to control. our results indicate that chronic PBM made by red laser has an important hypotensive effect in renovascular hypertensive models, by a mechanism that involves decrease in oxidative stress from vascular beds.

Caloric restriction improves inflammation in different tissues of the Wistar rats with obesity and 2K1C renovascular hypertension.

Renovascular hypertension (RHV) is the cause of high blood pressure due to left renal ischemia, and obesity and hypertension cause an inflammatory response. This work analyzed the inflammatory and tissue repair profile in renal, hepatic, and cardiac tissues in an animal model of RVH associated with a high-fat diet and caloric restriction. The expressions of RORγ-t, IL-17, T-bet, and TNF-α decreased and IFN-γ increased in the right kidney. In relation to the left kidney, caloric restriction decreased the expression of IFN-γ. In the liver, caloric restriction decreased RORγ-t, IL-17, and T-bet. Hypertension associated with obesity decreased the expression of IFN-γ, while caloric restriction increased. In the right kidney, hypertension and obesity, associated or not with caloric restriction, increased the area of collagen fibers. In the heart and liver, caloric restriction reduced the area of collagen fibers. Caloric restriction increased vascular endothelial growth factor, reduced levels of growth transformation factor-ß1 (TGF-ß), and increased collagen I in the left kidney. Hypertension/obesity, submitted or not having caloric restriction, increased TGF-ß in liver. The results suggest that caloric restriction has beneficial effects in lowering blood pressure and regulating tissue proinflammatory cytokines. However, there was no change in the structure and composition of tissue repair markers.

Atherosclerotic renovascular disease.

This review investigates patients with renovascular disease due to atherosclerotic renal artery stenosis. This group of patients has a very high risk of cardiovascular events. Randomised trials have failed to show that renal artery stenting is more effective than medical therapy alone in most patients but did not enroll patients with high-risk clinical syndromes. Recent cohort studies have observed a beneficial effect of renal artery stenting on blood pressure and kidney function in high-risk patients with atherosclerotic renovascular disease. Therefore, a Danish randomised trial has been initiated to explore these observations further.

Hipertensión como elemento común de trasplante renal con riñón presor y del síndrome de encefalopatía posterior reversible / Hypertension as a common element of renal transplantation with pressor kidney and posterior reversible encephalopathy syndrome

La hipertensión arterial secundaria supone solo un 5-10% de los casos de hipertensión arterial, de ahí la importancia de su sospecha clínica para el diagnóstico. Una de las causas más frecuentes de hipertensión secundaria es la hipertensión renovascular, que se produce por hipoperfusión renal y activación del sistema renina-angiotensina-aldosterona. Además de que la hipertensión arterial supone uno de los factores de riesgo cardiovasculares más prevalente en la población, su mal control puede producir alteraciones neurológicas agudas como el síndrome de leucoencefalopatía posterior reversible (PRES), en el que es característico la aparición de alteraciones visuales. A continuación, exponemos el caso de un paciente trasplantado renal con hipertensión arterial con empeoramiento secundario a estenosis de la arteria renal y desarrollo de PRES. (AU)

Secondary arterial hypertension accounts for only 5-10% of cases of arterial hypertension, hence the importance of its clinical suspicion for diagnosis. One of the most common causes of secondary hypertension is renovascular hypertension, caused by renal hypoperfusion and activation of the renin-angiotensin-aldosterone system. In addition to arterial hypertension being one of the most prevalent cardiovascular risk factors in the population, its poor control can cause acute neurological disorders such as Posterior Reversible Leukoencephalopathy syndrome (PRES), being characteristic the appearance of visuals alterations. Next, we present the case of a kidney transplant patient with well-controlled arterial hypertension with worsening secondary to renal artery stenosis and development of PRES. (AU)

Effects of aurantiamide on a rat model of renovascular arterial hypertension.

Asperglaucide (ASP) is an aurantiamide, an effective constituent of purslane (Portulaca oleracea L.), a safe to eat greenery. Effects of ASP on endothelial function, endothelial nitric oxide synthase (eNOS) expression, vascular fluidity, renal and vascular reactive oxygen, and nitrogen species (ROS/RNS) production was examined in the two-kidney one-clip (2 K-1C) rat model of renovascular arterial hypertension. ASP toxicity, dose dependent eNOS gene expression and protein levels were also analyzed in human umbilical vein endothelial cells (HUVEC). The 2 K-1C model of hypertension was created via surgery and mean blood pressure (MBP) was measured by tail-cuff method during four weeks of ASP treatment. Erythrocyte deformability was monitored by rotational ektacytometry, while vascular constrictor and dilator responses were determined in organ baths. eNOS gene expression and protein levels were assessed in thoracic aorta and HUVEC. MBP was significantly decreased in hypertensive rats treated with ASP. Endothelium dependent vascular dilator and constrictor responses were also considerably improved following ASP treatment. There was a notable increase in red blood cell deformability in hypertensive rats treated with ASP as compared to hypertensive rats alone. A significant increase was observed in eNOS gene expression and protein levels in both normotensive and hypertensive rats treated with ASP. Treatment of HUVEC with 3 µM ASP notably increased eNOS mRNA and protein levels. In conclusion, ASP lowered blood pressure, improved endothelium-mediated relaxation, decreased renovascular ROS/RNS production in hypertensive rats. ASP also increased eNOS protein expression in aorta and HUVEC at nontoxic doses. ASP may have future potential as an anti-hypertensive agent.

A novel index for measuring the impact of devices on hypertension.

A key limitation in assessing the therapeutic impact of non-pharmacological approaches to treating hypertension is the method of reporting outcomes. Reducing the medications required to achieve the same blood pressure may be reported separately to a reduction in the blood pressure without change in medication, and thus lessen the reported beneficial impact of treatment. This study aims to derive a novel scoring system to gauge the therapeutic impact of non-drug treatment of hypertension by utilising a combination of excessive blood pressure and the number of anti-hypertensives into a combined score-the hypertensive index (HTi). The hypertensive index was empirically derived based on the systolic blood pressure and number of antihypertensive drugs, and applied retrospectively to a cohort undergoing intervention for renovascular hypertension. Subgroup and receiver operating characteristic analyses were used to compare the HTi to traditional methods of reporting outcomes. Following intervention (99 patients), 46% had improvement in both medication load and blood pressure, 29% had benefit in blood pressure without reduction in medication load, 15% had reduction in medication load without significant change in blood pressure and 9% showed no benefit in either parameter. The HTi was superior in detecting benefit from intervention compared with measuring blood pressure or medication load alone (AUC 0.94 vs 0.85;0.84). The hypertensive index may be a more sensitive marker of treatment effect than assessing blood pressure measurements alone. The use of such scoring systems in future trial design may allow more accurate reporting of the effects of interventions for hypertension.

Acute inhibition of nicotinamide adenine dinucleotide phosphate oxidase in the commissural nucleus of the solitary tract reduces arterial pressure and renal sympathetic nerve activity in renovascular hypertension.

BACKGROUND: A growing body of evidence suggests that oxidative stress plays a role in the pathophysiology of hypertension. However, the involvement of the reactive oxygen species (ROS) in the commissural nucleus of the solitary tract (commNTS) in development the of hypertension remains unclear. METHOD: We evaluated the hemodynamic and sympathetic responses to acute inhibition of NADPH oxidase in the commNTS in renovascular hypertensive rats. Under anesthesia, male Holtzman rats were implanted with a silver clip around the left renal artery to induce 2-kidney 1-clip (2K1C) hypertension. After six weeks, these rats were anesthetized and instrumented for recording mean arterial pressure (MAP), renal blood flow (RBF), renal vascular resistance (RVR), and renal sympathetic nerve activity (RSNA) during baseline and after injection of apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor), NSC 23766 (RAC inhibitor) or saline into the commNTS. RESULTS: Apocynin into the commNTS decreased MAP, RSNA, and RVR in 2K1C rats. NSC 23766 into the commNTS decreased MAP and RSNA, without changing RVR in 2K1C rats. CONCLUSION: These results demonstrate that the formation of ROS in the commNTS is important to maintain sympathoexcitation and hypertension in 2K1C rats and suggest that NADPH oxidase in the commNTS could be a potential target for therapeutics in renovascular hypertension.

Targeting the adenosine monophosphate-activated protein kinase signalling pathway by bempedoic acid attenuates Angiotensin II-induced cardiac remodelling in renovascular hypertension in rats.

The crosstalk between the renin-angiotensin system and Adenosine monophosphate-activated protein kinase (AMPK) gained significant interest due to their involvement in the pathogenesis of several cardiovascular diseases. Angiotensin II (Ang II) plays a crucial role in developing cardiac remodelling by inducing energy imbalance, inflammation, oxidative and endoplasmic reticulum stress, and transforming growth factor-ß (TGF-ß)-induced fibrosis. Ang II directly or through extracellular signal-regulated kinase (ERK) activation impairs AMPK signalling with well-known antioxidant, anti-inflammatory, and anti-fibrotic effects. AIM: This study aimed to investigate the role of bempedoic acid, a novel antihyperlipidemic drug, in attenuating hypertension-induced cardiac remodelling in rats by modulating Ang II-induced damage and activating the AMPK signalling pathway. METHOD: Sixty adult male Sprague Dawley rats were randomly allocated into the Sham control group, Hypertensive group, Captopril group (30 mg/kg), and Bempedoic acid group (30 mg/kg). Hypertension was induced by left renal artery ligation in all groups except the Sham control group. Treatment with captopril and bempedoic acid started 14 days post-surgy and lasted two weeks. Finally, Hemodynamic measurements and electrocardiographic examination were done followed by heart tissue samples collection for biochemical, histopathological, and immunohistochemical examinations. KEY FINDINGS: Bempedoic acid preserved the cardiac function and electrocardiogram patterns. It inhibited endoplasmic reticulum stress, exhibited antioxidant activity, and increased endothelial nitric oxide synthase activity. Bempedoic acid interfered with ERK signalling pathways, including nuclear factor-κB and TGF-ß, exerting anti-inflammatory and anti-fibrotic effects. SIGNIFICANCE: These findings indicate the cardioprotective and antihypertrophic activity of bempedoic acid, which are suggested to result from energy-independent AMPK downstream signalling activation.