Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension

Castoldi, Giovanna; Carletti, Raffaella; Ippolito, Silvia; Stella, Andréa; Zerbini, Gianpaolo; Pelucchi, Sara; Zatti, Giovanni; Gioia, Cira Di

doi:10.3390/ijms222413678

Cited by 19 publications

(17 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ang II administration caused a significant increase in the heart/BW and kidney/BW ratios as compared to control rats, in line with the possible development of myocardial and kidney hypertrophy/fibrosis [ 15 , 16 , 17 ]. Losartan administration prevented the increase of heart and kidney/BW ratio in Ang II treated rats ( Table 1 ).…”

Section: Resultsmentioning

confidence: 95%

“…Non-fasting plasma glucose (mg/dL), creatinine (mg/dL), sodium (mEq/L), potassium (mEq/L), calcium (mg/dL), phosphate (mg/dL), alkaline phosphatase (U/L), uric acid (mg/dL), total cholesterol (mg/dL), triglycerides (mg/dL) and 24 h urinary calcium (mg/24 h), phosphate (mg/24 h), and sodium (mEq/24 h) were measured by colorimetric technique on Cobas Roche (Mannheim, Germany) [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

“…Besides the ‘classical’ systemic RAS, it has been demonstrated that the components of RAS are expressed in multiple tissues [ 12 ]. At the same time, Ang II, in addition to its well-known hemodynamic action, has many cellular effects in different tissues promoting inflammation [ 13 , 14 , 15 ], fibrosis [ 13 , 16 , 17 ], and hypertrophy [ 17 , 18 , 19 ], mainly mediated by AT1 receptors.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Angiotensin II Modulates Calcium/Phosphate Excretion in Experimental Model of Hypertension: Focus on Bone

et al. 2022

Self Cite

View full text Add to dashboard Cite

A link between hypertension and long-term bone health has been suggested. The aim of this study was to investigate the effects of chronic angiotensin II administration on urinary calcium/phosphate excretion, bone mineral density, bone remodeling and osteoblast population in a well-established experimental model of hypertension, in the absence of possible confounding factors that could affect bone metabolism. Male Sprague–Dawley rats, divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis, n = 8); (b) Ang II+losartan (Los, 50 mg/kg/day, per os, n = 6); (c) control group (physiological saline, sub cutis, n = 9); and (d) control+losartan (n = 6) were treated for four weeks. During the experimental period, 24-hour diuresis, urinary calcium, phosphate and sodium excretion were measured prior to the treatment, at two weeks of treatment, and at the end of the treatment. Systolic blood pressure was measured by plethysmography technique (tail cuff method). At the end of the experimental protocol, the rats were euthanized and peripheral quantitative computed tomography at the proximal metaphysis and at the diaphysis of the tibiae and quantitative bone histomorphometry on distal femora were performed. Angiotensin II-dependent hypertension is associated with increased calcium and phosphate excretion. AT1 receptor blockade prevented the increase of blood pressure and phosphate excretion but did not affect the increase of calcium excretion. These changes took place without significantly affecting bone density, bone histology or osteoblast population. In conclusion, in our experimental conditions, angiotensin II-dependent hypertension gave rise to an increased urinary excretion of calcium and phosphate without affecting bone density.

show abstract

Section: Resultsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Angiotensin II Modulates Calcium/Phosphate Excretion in Experimental Model of Hypertension: Focus on Bone

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Angiotensin II is known to stimulate NADPH oxidase activity via AT1 receptor. Sub-pressor dose of angiotensin II does not significantly raise blood pressure in wild-type mice ( 15 ) but promotes the inflammatory cell activation ( 16 ). We used low dose of angiotensin II infusion to stimulate the splenic cells in vivo .…”

Section: Resultsmentioning

confidence: 99%

Coupling of phagocytic NADPH oxidase activity and mitochondrial superoxide production

Dikalov

Dikalova²,

Kirilyuk³

2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Superoxide radical plays an important role in redox cell signaling and physiological processes; however, overproduction of superoxide or insufficient activity of antioxidants leads to oxidative stress and contributes to the development of pathological conditions such as endothelial dysfunction and hypertension. Meanwhile, the studies of superoxide in biological systems represent unique challenges associated with short lifetime of superoxide, insufficient reactivity of the superoxide probes, and lack of site-specific detection of superoxide. In this work we have developed 15N-and deuterium-enriched spin probe 15N-CAT1H for high sensitivity and site-specific detection of extracellular superoxide. We have tested simultaneous tracking of extracellular superoxide by 15N-CAT1H and intramitochondrial superoxide by conventional 14N-containing spin probe mitoTEMPO-H in immune cells isolated from spleen, splenocytes, under basal conditions or stimulated with inflammatory cytokines IL-17A and TNFα, NADPH oxidase activator PMA, or treated with inhibitors of mitochondrial complex I rotenone or complex III antimycin A. 15N-CAT1H provides two-fold increase in sensitivity and improves detection since EPR spectrum of 15N-CAT1 nitroxide does not overlap with biological radicals. Furthermore, concurrent use of cell impermeable 15N-CAT1H and mitochondria-targeted 14N-mitoTEMPO-H allows simultaneous detection of extracellular and mitochondrial superoxide. Analysis of IL-17A- and TNFα-induced superoxide showed parallel increase in 15N-CAT1 and 14N-mitoTEMPO signals suggesting coupling between phagocytic NADPH oxidase and mitochondria. The interplay between mitochondrial superoxide production and activity of phagocytic NADPH oxidase was further investigated in splenocytes isolated from Sham and angiotensin II infused C57Bl/6J and Nox2KO mice. Angiotensin II infusion in wild-type mice increased the extracellular basal splenocyte superoxide which was further enhanced by complex III inhibitor antimycin A, mitochondrial uncoupling agent CCCP and NADPH oxidase activator PMA. Nox2 depletion attenuated angiotensin II mediated stimulation and inhibited both extracellular and mitochondrial PMA-induced superoxide production. These data indicate that splenocytes isolated from hypertensive angiotensin II-infused mice are “primed” for enhanced superoxide production from both phagocytic NADPH oxidase and mitochondria. Our data demonstrate that novel 15N-CAT1H provides high sensitivity superoxide measurements and combination with mitoTEMPO-H allows independent and simultaneous detection of extracellular and mitochondrial superoxide. We suggest that this new approach can be used to study the site-specific superoxide production and analysis of important sources of oxidative stress in cardiovascular conditions.

show abstract

“…To narrow the mechanistic possibilities for the action of PRR inhibition on steatosis development, we performed the losartan study using treatment identical to that employed for the PRO20 treatment protocol. Losartan is an AT1R antagonist that competitively blocks the action of Ang II at AT1Rs at the dose employed in this study, leading to a decrease in blood pressure [33][34][35]. Administration of losartan has been shown to attenuate hepatic steatosis in some animal models; however, in other cases, no effect of this intervention on steatosis development, weight gain, or glucose handling was reported [36,37].…”

Section: Discussionmentioning

confidence: 99%

(Pro)Renin Receptor Antagonism Attenuates High-Fat-Diet–Induced Hepatic Steatosis in Non-Alcoholic Fatty Liver Disease

Gayban

Souza

Cooper

et al. 2022

Preprint

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we hypothesized that inhibition of the PRR would prevent the development of diet-induced hepatic steatosis and fibrosis. To test our hypothesis, we fed wild-type mice on a C57Bl/6J background either a high-fat diet (HFD; 60% calories from fat) or normal fat diet (NFD; 10% calories from fat) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis in C57BL/6J mice. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either PRO20, a peptide PRR antagonist, or scrambled peptide (700 ug/kg/d) for 4 or 6 weeks. We found that a 6-week HFD significantly increased liver lipid accumulation, as detected by Oil Red O staining, and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment significantly reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or glucose levels. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area detected by Sirius Red staining was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase (ALT), an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPARγ and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the mechanism by which PRR regulates lipid metabolism in the liver and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis development in NAFLD.

show abstract

Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension

Cited by 19 publications

References 37 publications

Angiotensin II Modulates Calcium/Phosphate Excretion in Experimental Model of Hypertension: Focus on Bone

Angiotensin II Modulates Calcium/Phosphate Excretion in Experimental Model of Hypertension: Focus on Bone

Coupling of phagocytic NADPH oxidase activity and mitochondrial superoxide production

(Pro)Renin Receptor Antagonism Attenuates High-Fat-Diet–Induced Hepatic Steatosis in Non-Alcoholic Fatty Liver Disease

Contact Info

Product

Resources

About