Diabetic Nephropathy Induced by Increased<i>Ace</i>Gene Dosage Is Associated with High Renal Levels of Angiotensin (1–7) and Bradykinin

Bertoncello, Nádia; Moreira, Roseli Peres; Arita, Danielle Yuri; Aragão, Danielle Sanches; Watanabe, Ingrid Kazue Mizuno; Dantas, Patrícia Sousa; Santos, Ralmony A; Mattar-Rosa, Rodolfo; Yokota, Rodrigo; Cunha, Tatiana Sousa; Casarini, Dulce Elena

doi:10.1155/2015/674047

Cited by 18 publications

(11 citation statements)

References 76 publications

(89 reference statements)

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“…33 In such local RAAS context, Ang-(1-7) could, thus, reach sufficient concentrations in tissues to regulate AT1-R activity. Ang- (1-7) could, thus, be found to reach 30 pmol/g in renal aorta of the Wistar Kyoto rat 34 and ≤200 pmol/g in mice kidney tissue or 300 pmol/g in diabetic mice, 35 a concentration comparable to the Ki of Ang-(1-7) for AT1-R in our study. Now, even in a local environment, given the higher affinity of Ang II for AT1-R compared with Ang-(1-7), the probability to favor the Ang-(1-7)/AT1-R axis over that of Ang II/AT-R axis will rely essentially on higher Ang-(1-7) concentrations than Ang II …”

Section: Discussionsupporting

confidence: 78%

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

et al. 2016

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Hyperactivity of the renin–angiotensin–aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin–angiotensin–aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown. In this study, we systematically determined efficacy and potency of Ang II, Ang III, Ang IV, and Ang-(1–7) in AT1-R–expressing HEK293T cells on the activation of cardiodeleterious G-proteins and cardioprotective β-arrestin2. Ang III and Ang IV fully activate similar G-proteins than Ang II, the prototypical AT1-R agonist, despite weaker potency of Ang IV. Interestingly, Ang-(1–7) that binds AT1-R fails to promote G-protein activation but behaves as a competitive antagonist for Ang II/Gi and Ang II/Gq pathways. Conversely, all renin–angiotensin–aldosterone system peptides act as agonists on the AT1-R/β-arrestin2 axis but display biased activities relative to Ang II as indicated by their differences in potency and AT1-R/β-arrestin2 intracellular routing. Importantly, we reveal Ang-(1–7) a known Mas receptor-specific ligand, as an AT1-R–biased agonist, selectively promoting β-arrestin activation while blocking the detrimental Ang II/AT1-R/Gq axis. This original pharmacological profile of Ang-(1–7) at AT1-R, similar to that of synthetic AT1-R–biased agonists, could, in part, contribute to its cardiovascular benefits. Accordingly, in vivo, Ang-(1–7) counteracts the phenylephrine-induced aorta contraction, which was blunted in AT1-R knockout mice. Collectively, these data suggest that Ang-(1–7) natural-biased agonism at AT1-R could fine-tune the physiology of the renin–angiotensin–aldosterone system.

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Section: Discussionsupporting

confidence: 78%

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

et al. 2016

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“…The eluted fractions were evaporated to dryness under a stream of nitrogen and resuspended in 500 μl mobile phase A (Bertoncello et al . ). The chromatographic separation of 20 μl was achieved by HPLC (Shimadzu System, Kyoto, Japan) in a reverse phase column 300SB C8 (150 mm length × 4.6 mm inner diameter, 5 μm particle size).…”

Section: Methodsmentioning

confidence: 97%

“…After sample introduction, columns were washed with water (10 ml), and peptides of interest were eluted with 1 ml of a mixture of ethanol, acetic acid and water (90:4:6). The eluted fractions were evaporated to dryness under a stream of nitrogen and resuspended in 500 μl mobile phase A (Bertoncello et al 2015). The chromatographic separation of 20 μl was achieved by HPLC (Shimadzu System, Kyoto, Japan) in a reverse phase column 300SB C8 (150 mm length × 4.6 mm inner diameter, 5 μm particle size).…”

Section: Quantification Of Angiotensin By Hplcmentioning

confidence: 99%

Exercise training modulates the hepatic renin–angiotensin system in fructose‐fed rats

Frantz

Medeiros

Giori

et al. 2017

Experimental Physiology

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What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100 g l ). After 2 weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min day , 4 days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and glycogen accumulation. Furthermore, exercise improved the response to the deleterious effects of HFr overload by normalizing the gluconeogenesis pathway and the protein levels of interleukin-6 and tumour necrosis factor-α. The HFr rats displayed increased hepatic ACE activity and protein expression and angiotensin II concentration, which were attenuated by exercise training. Exercise training restored the ACE2/angiotensin-(1-7)/Mas receptor axis. Exercise training may favour the counter-regulatory ACE2/angiotensin-(1-7)/Mas receptor axis over the classical RAS (ACE/angiotensin II/angiotensin II type 1 receptor axis), which could be responsible for the reduction of metabolic dysfunction and the prevention of non-alcoholic fatty liver disease.

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“…The peptidase is a membranebound and glycosylated protein (120 -180 kDa); however, soluble forms of the enzyme are present in the circulation, cerebrospinal fluid, lymph, and urine (15). ACE plays a key role in the formation of ANG II, but the peptidase metabolizes other peptides including bradykinin, substance P, acetyl-SerAsp-Lys-Pro, and ANG-(1-7) (16,145). ACE activity is typically measured by small peptide substrates such as hippurylHis-Leu or furylacrylol-Phe-Ala-Gly-Gly in a buffer containing chloride (10 -200 mM) and zinc (1-100 M) for optimal peptidase activity (24,122).…”

Section: Ras Protein Componentsmentioning

confidence: 99%

“…Therefore, a UV peak may be comprised of multiple species, and alterations in peak area between experimental groups cannot be readily attributed to one peptide. Moreover, the reported sensitivity or limit of quantitation of 3 pmol for the HPLC analysis is not adequate to detect authentic levels of endogenous peptides (16). ANG II and ANG-(1-7) values derived from these methods are typically far higher in plasma (26,33,51,135), kidney (33,110,114), vasculature (48), adipose tissue (33,115), and heart (42) than by RIA, HPLC-RIA, or HPLC-MS methods (Table 1).…”

Section: Ras Peptidesmentioning

confidence: 99%

Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

Chappell

2016

American Journal of Physiology-Heart and Circulatory Physiology

224

254

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Diabetic Nephropathy Induced by IncreasedAceGene Dosage Is Associated with High Renal Levels of Angiotensin (1–7) and Bradykinin

Cited by 18 publications

References 76 publications

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

Exercise training modulates the hepatic renin–angiotensin system in fructose‐fed rats

Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

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