Reduced plasma angiotensin II levels are reversed by hydroxyurea treatment in mice with sickle cell disease

Santos, Alisson Fernandes dos; Almeida, Camila B.; Brugnerotto, Ana Flávia; Roversi, Fernanda Marconi; Pallis, Flávia Rubia; Franco‐Penteado, Carla F.; Lanaro, Carolina; Albuquerque, Dulcinéia Martins; Leonardo, Flávia C.; Costa, Fernando Ferreira; Conran, Nicola

doi:10.1016/j.lfs.2014.08.021

Cited by 9 publications

(11 citation statements)

References 33 publications

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“…We hypothesize that high levels of ACE produces high levels of Ang II, resulting in Ang II‐induced glomerular damage and PA, even in childhood (Axelsson et al , ). Intense ligation and affinity of Ang II to AT 1 receptors would reduce urinary levels of Ang II, as previously reported in plasma Ang II of sickle cell mice (dos Santos et al , ). Excessive renal AT1 receptor stimulation would contribute to vasoconstriction in the vasa recta, mesangial proliferation and glomerular hypertrophy (Nath & Hebbel, ; Roy et al , ).…”

Section: Clinical and Laboratory Features Of Patients With Sickle Celsupporting

confidence: 68%

“…No studies have evaluated renin‐angiotensin system (RAS) components in patients with SCA, and whether RAS activity plays a role in albuminuria. Animal models of sickle cell disease (SCD) have demonstrated changes in the levels of RAS components (dos Santos et al , ; Roy et al , ). However, there is currently no data available regarding RAS molecules in humans with SCD, which is crucial to understand the role of RAS components in sickle cell nephropathy, and to identify therapeutic targets.…”

Section: Clinical and Laboratory Features Of Patients With Sickle Celmentioning

confidence: 99%

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Low urinary levels of angiotensin‐converting enzyme 2 may contribute to albuminuria in children with sickle cell anaemia

et al. 2018

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Section: Clinical and Laboratory Features Of Patients With Sickle Celsupporting

confidence: 68%

Section: Clinical and Laboratory Features Of Patients With Sickle Celmentioning

confidence: 99%

Low urinary levels of angiotensin‐converting enzyme 2 may contribute to albuminuria in children with sickle cell anaemia

et al. 2018

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“…The investigation of the tissue localized RAS is technically challenging, which is reflected by the heterogeneity of reported tissue angiotensin concentrations. The fluctuation of Ang II in plasma ranges over 3 orders of magnitude 23 24 25 while actual physiological levels range between 10 to 100 pg/ml 26 27 28 . To overcome some of the previous technical limitations, we used chemically identical isotope-labelled peptides as internal standards 29 30 for the multiplex liquid chromatography-tandem mass spectrometry (LC-MS/MS) based quantification of 10 angiotensin metabolites in plasma and tissue 27 31 .…”

mentioning

confidence: 99%

Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney

Domenig

Manzel

Grobe

et al. 2016

Sci Rep

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Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy.

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“…Mice were obtained from the animal house (CEMIB), at the University of Campinas. Animals were phenotyped to confirm graft success at 2 months post-transplant, according to [ 21 ], and were then used at the ages of 22 weeks (5 months; “young adults") and at 37 weeks (9 months; adults), according to [ 24 ]. Male mice were chosen for use in animal protocols due to the potential for modulation of the RAS by hormonal variations in females [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, inhibitors of ACE (ACEi) have been employed with a view to preventing or reducing kidney complications or chronic kidney disease in people with SCD [ 20 ]. In a previous study conducted by our research group, decreased expression of the gene encoding ACE in the kidneys of mice with SCD was observed, in association with decreased plasma levels of Ang II in the plasma of these mice [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Reduced blood pressure in sickle cell disease is associated with decreased angiotensin converting enzyme (ACE) activity and is not modulated by ACE inhibition

Brito

Santos²,

Chweih

et al. 2022

PLoS ONE

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Background Sickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD. Methods BP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR. Results Diastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice. Conclusion Relative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD.

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Reduced plasma angiotensin II levels are reversed by hydroxyurea treatment in mice with sickle cell disease

Cited by 9 publications

References 33 publications

Low urinary levels of angiotensin‐converting enzyme 2 may contribute to albuminuria in children with sickle cell anaemia

Low urinary levels of angiotensin‐converting enzyme 2 may contribute to albuminuria in children with sickle cell anaemia

Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney

Reduced blood pressure in sickle cell disease is associated with decreased angiotensin converting enzyme (ACE) activity and is not modulated by ACE inhibition

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