Alternative pathways for angiotensin II production as an important determinant of kidney damage in endotoxemia

Rosa, Rodolfo Mattar; Colucci, Juliana Almada; Yokota, Rodrigo; Moreira, Roseli Peres; Aragão, Danielle Sanches; Ribeiro, Amanda Aparecida; Arita, Danielle Yuri; Watanabe, Ingrid Kazue Mizuno; Palomino, Zaira; Cunha, Tatiana Sousa; Casarini, Dulce Elena

doi:10.1152/ajprenal.00121.2014

Cited by 21 publications

(13 citation statements)

References 40 publications

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“…Our results showed that there was no alteration of ACE activity, but increased chymase activity in FG in renal tissues, that associated with elevated Ang II concentrations suggest that alternative pathways were activated to produce this peptide, as has been shown to occur in the kidney under toxemia as described by Rosa et al (2016) . We can also confirmed that the enzymes tonin, cathepsin, and chymase are involved in this increase in Ang II levels ( Rosa et al, 2016 ). In our high fructose model of kidney damage, we believe that these enzymes may also be responsible for the high Ang II levels.…”

Section: Discussionsupporting

confidence: 57%

“…The samples were extracted using C 18 Sep-Pak columns and analyzed by HPLC. The peptide was separated by HPLC (Shimadzu System; Kyoto, Japan) using an Aquapore reversed-phase column (250 mm × 4.6 mm; ODS 300; 7 μm; PerkinElmer; São Paulo, São Paulo, Brazil), using a linear gradient (5–35%) of the mobile phase B (95% acetonitrile in 0.1% H 3 PO 4 ) at a 1.5 mL/min flow rate (40 min) ( Rosa et al, 2016 ). The HPLC column was calibrated under the same conditions using synthetic standards, and the peptides angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin 1-7 (Ang 1-7) were detected with absorbance (l = 214 nm).…”

Section: Methodsmentioning

confidence: 99%

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Intra-Renal Angiotensin Levels Are Increased in High-Fructose Fed Rats in the Extracorporeal Renal Perfusion Model

et al. 2018

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Overconsumption of fructose leads to metabolic syndrome as a result of hypertension, insulin resistance, and hyperlipidemia. In this study, the renal function of animals submitted to high fructose intake was analyzed from weaning to adulthood using in vivo and ex vivo methods, being compared with a normal control group. We investigated in ex vivo model of the role of the renin Angiotensin system (RAS) in the kidney. The use of perfused kidney from animals submitted to 8-week fructose treatment showed that high fructose intake caused metabolic and cardiovascular alterations that were consistent with other studies. Moreover, the isolated perfused kidneys obtained from rats under high fructose diet showed a 33% increase in renal perfusion pressure throughout the experimental period due to increased renal vascular resistance and a progressive fall in the glomerular filtration rate, which reached a maximum of 64% decrease. Analysis of RAS peptides in the high fructose group showed a threefold increase in the renal concentrations of angiotensin I (Ang I) and a twofold increase in angiotensin II (Ang II) levels, whereas no change in angiotensin 1-7 (Ang 1-7) was observed when compared with the control animals. We did not detect changes in angiotensin converting enzyme (ACE) activity in renal tissues, but there is a tendency to decrease. These observations suggest that there are alternative ways of producing Ang II in this model. Chymase the enzyme responsible for Ang II formation direct from Ang I was increased in renal tissues in the fructose group, confirming the alternative pathway for the formation of this peptide. Neprilysin (NEP) the Ang 1-7 forming showed a significant decrease in activity in the fructose vs. control group, and a tendency of reduction in ACE2 activity. Thus, these results suggest that the Ang 1-7 vasodilator peptide formation is impaired in this model contributing with the increase of blood pressure. In summary, rats fed high fructose affect renal RAS, which may contribute to several deleterious effects of fructose on the kidneys and consequently an increase in blood pressure.

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Section: Discussionsupporting

confidence: 57%

Section: Methodsmentioning

confidence: 99%

Intra-Renal Angiotensin Levels Are Increased in High-Fructose Fed Rats in the Extracorporeal Renal Perfusion Model

et al. 2018

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“…Angiotensins were extracted from the LV and plasma as previously described [ 22 , 23 ]. LV tissue was weighed and homogenized with 100 mmol/L PB, pH 7.2, containing 340 mmol/L sucrose, 300 mmol/L NaCl and a mix of proteases inhibitors (Complete Mini Roche).…”

Section: Methodsmentioning

confidence: 99%

Temporal changes in cardiac oxidative stress, inflammation and remodeling induced by exercise in hypertension: Role for local angiotensin II reduction

et al. 2017

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Exercise training reduces renin-angiotensin system (RAS) activation, decreases plasma and tissue oxidative stress and inflammation in hypertension. However, the temporal nature of these phenomena in response to exercise is unknown. We sought to determine in spontaneously hypertensive rats (SHR) and age-matched WKY controls the weekly effects of training on blood pressure (BP), plasma and left ventricle (LV) Ang II and Ang-(1–7) content (HPLC), LV oxidative stress (DHE staining), gene and protein expression (qPCR and WB) of pro-inflammatory cytokines, antioxidant enzymes and their consequence on hypertension-induced cardiac remodeling. SHR and WKY were submitted to aerobic training (T) or maintained sedentary (S) for 8 weeks; measurements were made at weeks 0, 1, 2, 4 and 8. Hypertension-induced cardiac hypertrophy was accompanied by acute plasma Ang II increase with amplified responses during the late phase of LV hypertrophy. Similar pattern was observed for oxidative stress markers, TNF alpha and interleukin-1β, associated with cardiomyocytes’ diameter enlargement and collagen deposition. SHR-T exhibited prompt and marked decrease in LV Ang II content (T1 vs T4 in WKY-T), normalized oxidative stress (T2), augmented antioxidant defense (T4) and reduced both collagen deposition and inflammatory profile (T8), without changing cardiomyocytes’ diameter and LV hypertrophy. These changes were accompanied by decreased plasma Ang II content (T2-T4) and reduced BP (T8). SHR-T and WKY-T showed parallel increases in LV and plasma Ang-(1–7) content. Our data indicate that early training-induced downregulation of LV ACE-AngII-AT1 receptor axis is a crucial mechanism to reduce oxidative/pro-inflammatory profile and improve antioxidant defense in SHR-T, showing in addition this effect precedes plasma RAS deactivation.

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“…We have similarly reported significant increases in renal arteriolar chymase-dependent ANG II formation in diabetic compared to control mice (Park et al, 2013), and functional evidence for enhanced chymase-dependent renal microvascular vasoconstriction (Harrison-Bernard et al, 2013;Park et al, 2010). We speculate that cathepsin G (Rosa et al, 2016), kallikrein, tonin, and elastase-2 may represent alternative pathways for angiotensin-converting enzyme-independent ANG II formation in this study (Uehara, Miura, & Yahiro, 2013). These findings are potentially of great relevance to the treatment of patients.…”

Section: Discussionmentioning

confidence: 52%

Chymase inhibition retards albuminuria in type 2 diabetes

et al. 2019

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Chymase released from mast cells produces pro‐fibrotic, inflammatory, and vasoconstrictor agents. Studies were performed to test the hypothesis that chronic chymase inhibition provides a renal protective effect in type 2 diabetes. Diabetic (db/db) and control mice (db/m) were chronically infused with a chymase‐specific inhibitor or vehicle for 8 weeks. Baseline urinary albumin excretion (UalbV) averaged 42 ± 3 and 442 ± 32 microg/d in control (n = 22) and diabetic mice (n = 27), respectively (p < .05). After administration of chymase inhibitor to diabetic mice, the change in UalbV was significantly lower (459 ± 57 microg/d) than in vehicle‐treated diabetic mice (645 ± 108 microg/d). UNGALV was not different at baseline between diabetic mice that would receive the chymase inhibitor (349 ± 56 ng/d, n = 6) and vehicle (373 ± 99 ng/d, n = 6) infusions, but increased significantly only in the vehicle‐treated diabetic mice (p < .05). Glomeruli of diabetic kidneys treated chronically with chymase inhibition demonstrated reduced mesangial matrix expansion compared to glomeruli from untreated diabetic mice. Plasma angiotensin II levels were not altered by chymase inhibitor treatment. In summary, chronic chymase inhibition slowed the progression of urinary albumin excretion in diabetic mice. In conclusion, renal chymase may contribute to the progression of albuminuria in type 2 diabetes renal disease.

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Alternative pathways for angiotensin II production as an important determinant of kidney damage in endotoxemia

Cited by 21 publications

References 40 publications

Intra-Renal Angiotensin Levels Are Increased in High-Fructose Fed Rats in the Extracorporeal Renal Perfusion Model

Intra-Renal Angiotensin Levels Are Increased in High-Fructose Fed Rats in the Extracorporeal Renal Perfusion Model

Temporal changes in cardiac oxidative stress, inflammation and remodeling induced by exercise in hypertension: Role for local angiotensin II reduction

Chymase inhibition retards albuminuria in type 2 diabetes

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