Idebenone protects the kidneys of rats with renovascular arterial hypertension by inhibiting oxidative stress and apoptosis.

Here, the protective effect of antioxidant Idebenone (IDB) on renovascular hypertension was studied. The two-kidney one-clip (2K-1C) model of renal hypertension was established. The rats were divided into 3 groups: sham-operation group, 2K-1C renal hypertensive rats' model group and model treated with IDB group. The mean arterial blood pressure (MBP) of rats was measured and pathological condition of kidney was observed by H&E staining. The change of renal damage biomarkers (Cre, BUN, urine proteins), inflammatory factors (IL-6, IL-1ß and TNF-α), oxidative stress ratio and key factors (MDA, SOD and CAT) were assessed by kits. The apoptosis key proteins (BAD, BAX, Caspase9, GSK-3ß) were detected via Western blot. The 2K-1C model of renal hypertension was established. IDB reduced the MBP, Cre, BUN, urine proteins and improved the pathological condition of 2K-1C kidney. IDB restrained the inflammation factors (IL-6, IL-1ß and TNF-α) and oxidative stress in kidney of renal hypertensive rats' model. Besides, IDB suppressed the expression of apoptosis key factors (BAD, BAX, Caspase9, GSK-3ß) in kidney of renal hypertensive rats' model. IDB protects the kidneys of rats with renovascular arterial hypertension by inhibiting inflammation, oxidative stress, and apoptosis. These findings might provide medication guidance for IDB in renovascular arterial hypertension.

Activation AMPK in Hypothalamic Paraventricular Nucleus Improves Renovascular Hypertension Through ERK1/2-NF-κB Pathway.

Hypertension is a globally prevalent disease, but the pathogenesis remains largely unclear. AMP-activated protein kinase (AMPK) is a nutrition-sensitive signal of cellular energy metabolism, which has a certain influence on the development of hypertension. Previously, we found a down-regulation of the phosphorylated (p-) form of AMPK, and the up-regulation of the angiotensin II type 1 receptor (AT1-R) and that of p-ERK1/2 in the hypothalamic paraventricular nucleus (PVN) of hypertensive rats. However, the exact mechanism underlying the relationship between AMPK and AT1-R in the PVN during hypertension remains unclear. Thus, we hypothesized that AMPK modulates AT1-R through the ERK1/2-NF-κB pathway in the PVN, thereby inhibiting sympathetic nerve activity and improving hypertension. To examine this hypothesis, we employed a renovascular hypertensive animal model developed via two-kidney, one-clip (2K1C) and sham-operated (SHAM). Artificial cerebrospinal fluid (aCSF), used as vehicle, or 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, an AMPK activator, 60 µg/day) was microinjected bilaterally in the PVN of these rats for 4 weeks. In 2K1C rats, there an increase in systolic blood pressure (SBP) and circulating norepinephrine (NE). Also, the hypertensive rats had lowered expression of p-AMPK and p-AMPK/AMPK, elevated expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R, increased NF-κB p65 activity in the PVN compared with the levels of these biomarkers in SHAM rats. Four weeks of bilateral PVN injection of AMPK activator AICAR, attenuated the NE level and SBP, increased the expression of p-AMPK and p-AMPK/AMPK, lessened the NF-κB p65 activity, decreased the expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R in the PVN of 2K1C rats. Data from this study imply that the activation of AMPK within the PVN suppressed AT1-R expression through inhibiting the ERK1/2-NF-κB pathway, decreased the activity of the sympathetic nervous system, improved hypertension.

The hydrogen sulfide donor 4-carboxyphenyl-isothiocyanate decreases blood pressure and promotes cardioprotective effect through reduction of oxidative stress and nuclear factor kappa B/matrix metalloproteinase (MMP)-2 axis in hypertension.

AIMS: Our aim was to evaluate whether the hydrogen sulfide (H2S) donor, 4-carboxyphenyl-isothiocyanate (4-CPI), exerts cardioprotective effect in the two kidney- one clip (2K-1C) rats through oxidative stress and MMP-2 activity attenuation and compare it with the classical H2S donor, Sodium Hydrosulfide (NaHS). MATERIALS AND METHODS: Renovascular hypertension (two kidneys-one clip; 2K-1C) was surgically induced in male Wistar rats. After two weeks, normotensive (2K) and hypertensive rats were intraperitoneally treated with vehicle (0.6 % dimethyl sulfoxide), NaHS (0.24 mg/Kg/day) or with 4-CPI (0.24 mg/Kg/day), for more 4 weeks. Systolic blood pressure (SBP) was evaluated weekly by tail-cuff plethysmography. Heart function was assessed by using the Millar catheter. Cardiac hypertrophy and fibrosis were evaluated by hematoxylin and eosin, and Picrosirius Red staining, respectively. The H2S was analyzed using WSP-1 fluorimetry and the cardiac oxidative stress was measured by lucigenin chemiluminescence and Amplex Red. MMP-2 activity was measured by in-gel gelatin or in situ zymography assays. Nox1, gp91phox, MMP-2 and the phospho-p65 subunit (Serine 279) nuclear factor kappa B (NF-κB) levels were evaluated by Western blotting. KEY FINDINGS: 4-CPI reduced blood pressure in hypertensive rats, decreased cardiac remodeling and promoted cardioprotection through the enhancement of cardiac H2S levels. An attenuation of oxidative stress, with inactivation of the p65-NF-κB/MMP-2 axis was similarly observed after NaHS or 4-CPI treatment in 2K-1C hypertension. SIGNIFICANCE: H2S is a mediator that promotes cardioprotective effects and decreases blood pressure, and 4-CPI seems to be a good candidate to reverse the maladaptive remodeling and cardiac dysfunction in renovascular hypertension.

Fenofibrate reduces cardiac remodeling by mitochondrial dynamics preservation in a renovascular model of cardiac hypertrophy.

Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.

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.

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.

Antihypertensive and Antioxidant Effects of an Aqueous Extract of Asafetida in Renovascular Hypertensive Rats.

Recently, the effect of an aqueous extract of asafetida on acute angiotensin II hypertensive rats was evaluated. The present study evaluated the antihypertensive and antioxidant effects of asafetida on a rat model of renovascular hypertension (RVH) using four groups. RVH was induced by clipping the renal artery; the sham group underwent surgery but without clipping. The RVH rats received losartan (Los, an AT1 receptor antagonist) or asafetida by gavage for 4 weeks. On the 28th day, the femoral artery was cannulated, and the systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) were recorded. Finally, the levels of superoxide dismutase (SOD) activity, malondialdehyde (MDA), and total thiol content in the kidney and heart tissues were measured. In RVH rats, SBP and MAP significantly increased compared with the control. Los and the extract significantly reduced the changes in SBP, MAP, and HR that were induced in the RVH rats (P <0.05-0.001). In RVH rats, levels of MDA significantly increased and the content of total thiol and SOD decreased in both the heart and kidney tissues. Los plus the extract significantly decreased MDA and increased total thiol and SOD in the heart and kidney tissues. We concluded that an aqueous extract of asafetida gum has antihypertensive and antioxidant effects in the RVH rat model. The effect of the extract is similar to that of Los, which suggests that this effect of asafetida is mediated via an effect on the angiotensin Type I receptor.

Hipertensión arterial renovascular secundaria a arteritis de Takayasu / Renovascular hypertension secondary to Takayasu arteritis

La hipertensión arterial (HTA) secundaria consiste en un aumento de la presión arterial debido a una causa identificable. Se estima una prevalencia alrededor del 5-15% de las personas con HTA. La búsqueda de HTA secundaria en todos los pacientes hipertensos no es viable ni costo-efectiva. Sin embargo, hay una serie de características que obligan a descartarla, como son el debut de HTA antes de los 40 años, empeoramiento agudo de HTA, HTA resistente, presencia de amplia lesión de órgano diana o alteraciones clínicas-analíticas, etc. Es importante detectar a estos pacientes ya que los tratamientos pueden ser curativos, especialmente en jóvenes. Presentamos el caso de un varón de 46 años que debutó con una urgencia hipertensiva y hemorragia subaracnoidea por rotura aneurismática. El estudio de causas secundarias resultó diagnóstico para una estenosis de la arteria renal debida a una arteritis de Takayasu en estadio cicatricial

Secondary arterial hypertension (HT) is an increase in blood pressure due to a recognisable cause. It is estimated that the prevalence of people with HT is around 5%-15%. The search for secondary HT in all hypertensive patients is neither feasible nor cost-effective. However, there are a series of signs that force us to discount its diagnosis such as newly diagnosed hypertension before the age of 40, acute worsening of hypertension, resistant hypertension, the presence of extensive organ injury or clinical-analytical alterations, etc. It is important to diagnosis these patients since treatments can be curative, especially in young people. We present the case of a 46-year-old man with hypertensive emergency and subarachnoid haemorrhage due to aneurysmal rupture. The study of secondary causes was diagnostic for renal artery stenosis due to Takayasu arteritis in the scarring stage

Hipertensión renovascular en un paciente con arteritis de Takayasu / Renovascular hypertension in a patient with Takayasu arteritis

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The Labdane Ent-3-Acetoxy-Labda-8(17), 13-Dien-15-Oic Decreases Blood Pressure In Hypertensive Rats / O Labdano Ácido Ent-3-Acetóxi-Labda-8(17), 13-Dieno-15-Óico Reduz Pressão Arterial Em Ratos Hipertensos

Abstract Background: Labdane-type diterpenes induce lower blood pressure via relaxation of vascular smooth muscle; however, there are no studies describing the effects of labdanes in hypertensive rats. Objective: The present study was designed to investigate the cardiovascular actions of the labdane-type diterpene ent-3-acetoxy-labda-8(17), 13-dien-15-oic acid (labda-15-oic acid) in two-kidney 1 clip (2K-1C) renal hypertension. Methods: Vascular reactivity experiments were performed in aortic rings isolated from 2K-1C and normotensive (2K) male Wistar rats. Nitrate/nitrite (NOx) measurement was performed in aortas by colorimetric assay. Blood pressure measurements were performed in conscious rats. Results: Labda-15-oic acid (0.1-300 µmol/l) and forskolin (0.1 nmol/l - 1 µmol/l) relaxed endothelium-intact and endothelium-denuded aortas from both 2K-1C and 2K rats. Labda-15-oic acid was more effective at inducing relaxation in endothelium-intact aortas from 2K pre-contracted with phenylephrine when compared to the endothelium-denuded ones. Forskolin was more potent than labda-15-oic acid at inducing vascular relaxation in arteries from both 2K and 2K-1C rats. Labda-15-oic acid-induced increase in NOx levels was lower in arteries from 2K-1C rats when compared to 2K rats. Intravenous administration of labda-15-oic acid (0.3-3 mg/kg) or forskolin (0.1-1 mg/kg) induced hypotension in conscious 2K-1C and 2K rats. Conclusion: The present findings show that labda-15-oic acid induces vascular relaxation and hypotension in hypertensive rats.

Resumo Fundamento: Diterpenos do tipo labdano induzem uma queda da pressão arterial por meio do relaxamento do músculo liso vascular; todavia, não há estudos que descrevam os efeitos de labdanos em ratos hipertensos. Objetivo: O presente estudo foi desenvolvido para investigar as ações cardiovasculares do labdano ácido ent-3-acetóxi-labda-8(17),13-dieno-15-óico (labda-15-óico) na hipertensão renal dois rins-1 clipe (2R-1C). Métodos: Foram feitos experimentos de reatividade vascular em anéis aórticos isolados de ratos machos 2R-1C e normotensos (2R). A medição de Nitrato/Nitrito (NOx) foi feita nas aortas por meio de ensaio colorimétrico. As medidas de pressão arterial foram feitas em ratos conscientes. Resultados: O ácido labda-15-óico (0,1 - 300 µmol/l) e a forscolina (0,1 nmol/l - 1 µmol/l) relaxaram as aortas com endotélio intacto e as aortas sem endotélio dos ratos 2R-1C e 2R. O labda-15-óico mostrou-se mais eficaz na indução do relaxamento em aortas com endotélio intacto de 2R pré-contraídas com fenilefrina em comparação àquelas sem endotélio. A forscolina mostrou-se mais potente do que o ácido labda-15-óico na indução do relaxamento vascular nas artérias tanto de ratos 2R-1C quanto de ratos 2R. O aumento dos níveis de NOx induzido pelo ácido labda-15-óico foi menor nas artérias de ratos 2R-1C em comparação a ratos 2R. A administração intravenosa de ácido labda-15-óico (0,3-3 mg/kg) ou forscolina (0,1-1 mg/kg) induziu hipertensão em ratos 2R-1C e 2R conscientes. Conclusão: Os presentes resultados mostram que o labda-15-óico induz relaxamento vascular e hipotensão em ratos hipertensos.

Infarto renal agudo: complicación de displasia fibromuscular / Acute renal infarction: complication of fibromuscular dysplasia

La hipertensión renovascular (HTRV) es una de las formas identificables de hipertensión arterial (HTA). A pesar de que la mayoría de las lesiones renovasculares corresponden a aterosclerosis, la displasia fibromuscular (DFM) es la principal causa en el resto de los casos. La fibrodisplasia de la capa media suele ser la lesión más común y presenta un curso menos progresivo. La afectación intimal y periarterial es menos frecuente pero presenta una evolución más rápida hacia la oclusión arterial, pudiendo ocasionar infarto en diferentes localizaciones. Presentamos el caso de una mujer diagnosticada de HTRV en relación con DFM complicada con infarto renal derecho por oclusión de arteria renal

Renovascular hypertension (RVHT) is one of the forms of identifiable hypertension. Whereas most renovascular lesions are caused by atherosclerosis, in the remaining cases fibromuscular dysplasia is the causative factor. Fibrous dysplasia of the tunica media is generally the most common lesion and a progressive course may be less frequently seen. Intimal and periarterial lesions are less common but usually show rapid progression to arterial occlusion, and can cause infarction of several systems. We report the case of a woman with RVHT secondary to fibromuscular dysplasia complicated with renal infarction

Fracaso renal agudo en paciente hipertenso / Acute renal failure and hypertension

Los pacientes hipertensos con nefropatía isquémica pueden presentar deterioroagudo de función renal por varias razones, entre ellas tratamiento con IECAs oARAII, deshidratación y oclusión de las arterias renales. Presentamos un caso de hipertensiónarterial secundaria a estenosis bilateral de arterias renales, tratada conARAII (valsartán), que presenta un deterioro agudo de función renal que precisadiálisis. La revascularización mediante angioplastia y colocación de «stent», junto ahidratación y supresión de este fármaco consigue la mejoría y estabilización prolongadade la función renal

Ischemic nephropathy could be complicated with hypertension and acute worseningof chronic renal failure secondary to ACE inhibitors or AT1 receptor antagonisttreatments and arterial occlusion. We describe a patient with bilateral renal arterystenosis and hypertension treated with AT1 receptor antagonist (valsartan) that developedrapid worsening of renal function that required dialysis. Percutaneous transluminalrenal artery angioplasty and stenting, complemented with hydratation andvalsartan suppression achieves rapid and sustained recovery of renal function

Síndrome antifosfolipídico primario e HTA maligna / Antiphospholipid síndrome associated to malignat hypertension

El síndrome antifosfolipídico viene definido por la presencia de anticuerpos antifosfolípidos y trombosis de repetición, siendo más prevalentes las trombosis venosas que las arteriales. La afectación renal en el síndrome antifosfolipídico primario es poco frecuente, oscilando entre un 20-25% de los casos y siendo la trombosis de la arteria renal principal un acontecimiento raramente descrito. Presentamos el caso de una mujer de 39 años, con historia previa de trombosis de repetición y diagnosticada de síndrome antifosfolipídico primario, que desarrolló hipertensión arterial maligna en el contexto de una oclusión de la arteria renal. Presentaba anticuerpos anticardiolipina IgG positivos a títulos elevados, anticoagulante lúpico positivo. El renograma isotópico objetivó una asimetría en la captación renal (60% a nivel del riñón derecho y un 40% a nivel del riñón izquierdo). La arteriografía renal detectó una trombosis pre-oclusiva de la arteria renal izquierda. Se consiguió un control óptimo de la presión arterial mediante el tratamiento con inhibidores de la ECA y alfa-bloqueantes (AU)

The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies and recurrent thrombosis, affecting the venous system more frequently than the arterial one. Renal involvement is only observed in approximatelly 20- 25% of cases, main renal artery thrombosis has been exceptionally described. We report a 39 year old woman with previous history of recurrent thrombosis diagnosed as primary antiphospholipid syndrome, who presented malignant hypertension in the context of a renal artery thrombosis. She had a high IgG anticardiolipin antibodies title and positive lupic anticoagulant. An isotopic renogram demonstrated assymetrical activity (60% right vs 40% left kidney). Renal arteriography demonstrated preoclusive thrombosis in the left renal artery. Blood pressure was well controlled by the use of ACE-inhibitor and alfablockers (AU)

Autotrasplante renal en la infancia / Kidney autotransplantation in childhood

Se presenta una paciente de 8 años de edad, de sexo femenino, con hipertensión arterial severa secundaria a estenosis de la arteria renal izquierda. Los estudios complementarios revelaron buena funcionalidad del riñón afectado y por la ubicación de la estenosis se realizó cirugía de autotransplante con muy buena evolución posterior

Autotrasplante renal en la infancia / Kidney autotransplantation in childhood

Se presenta una paciente de 8 años de edad, de sexo femenino, con hipertensión arterial severa secundaria a estenosis de la arteria renal izquierda. Los estudios complementarios revelaron buena funcionalidad del riñón afectado y por la ubicación de la estenosis se realizó cirugía de autotransplante con muy buena evolución posterior (AU)