Endogenous angiotensin II modulates nNOS expression in renovascular hypertension

Pereira, Thiago de Melo Costa; Balarini, Camille M.; Silva, I.V.; Cabral, Antônio M.; Vasquez, Elisardo C.; Meyrelles, Silvana S.

doi:10.1590/s0100-879x2009000700014

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…In contrast with plasma [60], NO levels in the stenotic kidney of 2K1C mice were not decreased, probably due to compensatory actions elicited by angiotensin II and hypoperfusion. This hypothesis is corroborated by findings from us and from others demonstrating an upregulation of nNOS in clipped kidneys in the 2K1C model [1] and an increase of renal eNOS activity in the angiotensin II infusion model [61]. In contrast with studies in 2K1C rats, in which sildenafil did not modify the low plasma NO levels [60], here we are demonstrating that in stenotic kidney from 2K1C mice sildenafil increases 1.7-fold the levels of NO and reduces the overproduction of •O 2 – and H 2 O 2 .…”

Section: Discussionsupporting

confidence: 86%

“…Renal artery stenosis, the main cause of chronic renovascular disease, is associated with significant metabolic alterations in the kidney, such as increased renin synthesis and reduction of nitric oxide (NO) sensitivity and cGMP content [1,2], apoptosis and atrophy [3,4]. Recently, it has become evident that oxidative stress is one of the most important mechanisms involved in renal hypoperfusion.…”

Section: Introductionmentioning

confidence: 99%

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Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

et al. 2014

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BackgroundOxidative stress and DNA damage have been implicated in the pathogenesis of renovascular hypertension induced by renal artery stenosis in the two-kidney, one-clip (2K1C) Goldblatt model. Considering our previous report indicating that the chronic blockade of phosphodiesterase 5 with sildenafil (Viagra®) has marked beneficial effects on oxidative stress and DNA damage, we tested the hypothesis that sildenafil could also protect the stenotic kidneys of 2K1C hypertensive mice against oxidative stress and genotoxicity.MethodsThe experiments were performed with C57BL6 mice subjected to renovascular hypertension by left renal artery clipping. Two weeks after clipping, the mice were treated with sildenafil (40 mg/kg/day for 2 weeks, 2K1C-sildenafil group) or the vehicle (2K1C). These mice were compared with control mice not subjected to renal artery clipping (Sham). After hemodynamic measurements, the stenotic kidneys were assessed using flow cytometry to evaluate cell viability and the comet assay to evaluate DNA damage. Measurements of intracellular superoxide anions and hydrogen peroxide levels as well as nitric oxide bioavailability were also obtained.ResultsSildenafil treatment significantly reduced mean arterial pressure (15%), heart rate (8%), intrarenal angiotensin II (50%) and renal atrophy (36%). In addition, it caused a remarkable decrease of reactive oxygen species production. On the other hand, sildenafil increased nitric oxide levels relative to those in the nontreated 2K1C mice. Sildenafil treatment also significantly reduced the high level of kidney DNA damage that is a characteristic of renovascular hypertensive mice.ConclusionsOur data reveal that sildenafil has a protective effect on the stenotic kidneys of 2K1C mice, suggesting a new use of phosphodiesterase 5 inhibitors for protection against the DNA damage observed in the hypoperfused kidneys of individuals with renovascular hypertension. Further translational research is necessary to delineate the mechanisms involved in the prevention of renal stenosis in the clinical setting.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

et al. 2014

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“…Expression of neuronal isoform of the enzyme nitric oxide synthase (nNOS) was performed by Western Blot, as previously described [ 40 ]. Briefly, after perfusion, kidneys were homogenized with a protease inhibitor cocktail (Product #P2714, Sigma Aldrich, St Louis, USA) and centrifuged at 11,000 rpm for 20 minutes at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Hypercholesterolemia promotes early renal dysfunction in apolipoprotein E-deficient mice

et al. 2011

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BackgroundAging and dyslipidemia are processes which can lead to deleterious consequences to renal function. Therefore, the aim of this study was to determine the effects of both hypercholesterolemia and aging on renal function in mice.MethodsMale hypercholesterolemic apolipoprotein E-deficient mice (ApoE, n = 13) and age-matched C57BL/6 control mice (C57, n = 15) were studied at 2 (young) and 8 (adult) month-old. At each time point, animals were placed in metabolic cages for 24 hours to urine volume and urinary creatinine quantification. Blood samples were collected for serum cholesterol, urea and creatinine measurements. Glomerular filtration rate (GFR) was estimated through creatinine clearance determination. Mesangial expansion was evaluated by Periodic Acid Schiff staining, renal fibrosis was determined through Masson's trichrome staining and neuronal nitric oxide synthase (nNOS) expression in the kidney was performed by Western Blotting. To statistical analysis two-way ANOVA followed by Fisher's post hoc test was used.ResultsTotal plasma cholesterol was increased about 5-fold in ApoE mice at both time points compared to C57 animals. At 2-month-old, GFR was already markedly reduced in ApoE compared to C57 mice (187 ± 28 vs 358 ± 92 μL/min, p < 0.05). Adult C57 (-77%) and ApoE (-50%) mice also presented a significant reduction of GFR. In addition, serum urea was significantly increased in young ApoE animals compared to C57 mice (11 ± 1.3 vs 7 ± 0.9 mmol/L, p < 0.01). A significant mesangial expansion was observed at 2-month old ApoE mice compared to C57 mice (35 ± 0.6 vs 30 ± 0.9%, respectively, p < 0.05), which was aggravated at 8-month old animals (40 ± 3 and 35 ± 3%, respectively). Tubulointersticial fibrosis was augmented at both young (17 ± 2%, p < 0.05) and adult (20 ± 1%, p < 0.05) ApoE mice compared to respective C57 age controls (8 ± 1 and 12 ± 2%, respectively). The expression of nNOS was markedly reduced in a time-dependent manner in both strains.ConclusionsThese data show that both hypercholesterolemia and aging contribute to the loss of renal function in mice.

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“…Three decades later, the rat became the main experimental model of 2K1C hypertension in our and other laboratories [9-11]. However, genetic discoveries and advances in molecular biotechnologies have provided the opportunity to develop mouse models of cardiovascular diseases, which has led to an increasing number of studies using this murine model of hypertension [12-15].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension

et al. 2014

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BackgroundThe clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance.Methods2K1C hypertension was induced in C57BL/6 mice. Two weeks later, they were treated with sildenafil (40 mg/kg/day, via oral) or vehicle for 2 weeks and compared with sham mice. At the end of the treatment, the levels of plasma and intrarenal Ang peptides were measured. Endothelial function and ROS production were assessed in mesenteric arterial bed (MAB).ResultsThe 2K1C mice exhibited normal plasma levels of Ang I, II and 1–7, whereas the intrarenal Ang I and II were increased (~35% and ~140%) compared with the Sham mice. Sildenafil normalized the intrarenal Ang I and II and increased the plasma (~45%) and intrarenal (+15%) Ang 1–7. The 2K1C mice exhibited endothelial dysfunction, primarily due to increased ROS and decreased NO productions by endothelial cells, which were ameliorated by treatment with sildenafil.ConclusionThese data suggest that the effects of sildenafil on endothelial dysfunction in 2K1C mice may be due to interaction with RAS and restoring NO/ROS balance in the endothelial cells from MAB. Thus, sildenafil is a promising candidate drug for the treatment of hypertension accompanied by endothelial dysfunction and kidney disease.

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Endogenous angiotensin II modulates nNOS expression in renovascular hypertension

Cited by 9 publications

References 34 publications

Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

Hypercholesterolemia promotes early renal dysfunction in apolipoprotein E-deficient mice

Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension

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