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1.
Chem Biol Interact ; 348: 109653, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34516974

RESUMO

Angiotensin II, the effector peptide of the renin-angiotensin system, is not only a pivotal peptide implicated in the regulation of blood pressure but also a key mediator of the inflammatory processes that play an important role in the pathology of hypertension-related cSVD. Harpagide is the major bioactive constituent of Scrophulariae Radix widely used in traditional Chinese medicine for numerous diseases including hypertension. The present study aimed to investigate the effect of harpagide on Ang II-induced neuroinflammation and the potential mechanism. Pretreated with harpagide or resatorvid (the TLR4 pathway inhibitor), BV2 cells were treated with Ang II or LPS (the TLR4 activator). NO, pro-inflammatory cytokines, the proteins on TLR4/MyD88/NF-κB signaling pathway and the expression of CD86, CD206, TREM2 in BV2 cells were detected respectively. Subsequently, the effects of harpagide on neurotoxicity and BBB destruction triggered by Ang II-induced neuroinflammation were investigated in the co-cultures of BV2 microglia/HT22 hippocampal neurons, BV2 microglia/bEnd.3 endotheliocyte and BV2 microglia/BBB monolayer model. We found that Ang II converted microglia into M1 state and resulted in neuroinflammation through activating TLR4/MyD88/NF-κB signaling pathway. It also triggered the imbalance of TLR4/TREM2 in microglia. Ang II-mediated inflammation microglia further led to neuronal apoptosis and BBB damage. Harpagide showed the effect of alleviating Ang II-mediated neuroinflammation as well as the resulting neurotoxicity and BBB destruction through inhibiting the TLR4/MyD88/NF-κB pathway. The anti-inflammatory and neuroprotective effect of harpagide suggested that it might be a potential therapeutic strategy in hypertensive cSVD.


Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Glicosídeos Iridoides/farmacologia , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular , Humanos , Microglia/citologia , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Receptor 4 Toll-Like/metabolismo
2.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502113

RESUMO

The renin-angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT1R) and type 2 (AT2R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT1R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT1R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT1R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT1R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II-AT1R axis.


Assuntos
Angiotensina II/farmacologia , Condrócitos/efeitos dos fármacos , Agrecanas/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Condrócitos/fisiologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Feminino , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo
3.
J Agric Food Chem ; 69(36): 10536-10549, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34460247

RESUMO

An emerging inference is that vascular cells transfer their biological cargo to recipient cells by secretion of extracellular vesicles (EVs). This study explored the effects of EVs produced from VSMCs with Ang II (EVs-A) or LSW + Ang II on HUVECs. The EVs-A increase ROS production, activate inflammation, and upregulate the expression of adhesion molecules. Among the EVs-A, miR-22, miR-143, miR-144, and miR-155 were significantly downregulated, while VSMCs pre-incubated with LSW could produce improved EVs. RNA sequencing revealed differential expression of genes associated with endothelial dysfunction, including the TNF signaling pathway, NOD-like receptor signaling pathway, NF-κB signaling pathway, and fluid shear stress and atherosclerosis pathway. Finally, we found that LSW could improve endothelial function by repairing the expression of miRNAs in VSMCs. It also suggests a potential mechanism for the injury action of endogenous peptide Ang II and protective effects of exogenous peptide LSW on vascular endothelial cells.


Assuntos
Angiotensina II , Vesículas Extracelulares , Angiotensina II/farmacologia , Anti-Hipertensivos , Células Endoteliais da Veia Umbilical Humana , Humanos , Soja
4.
Theranostics ; 11(16): 7995-8007, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335976

RESUMO

Rationale: The conserved long non-coding RNA (lncRNA) myocardial infarction associate transcript (Miat) was identified for its multiple single-nucleotide polymorphisms that are strongly associated with susceptibility to MI, but its role in cardiovascular biology remains elusive. Here we investigated whether Miat regulates cardiac response to pathological hypertrophic stimuli. Methods: Both an angiotensin II (Ang II) infusion model and a transverse aortic constriction (TAC) model were used in adult WT and Miat-null knockout (Miat-KO) mice to induce pathological cardiac hypertrophy. Heart structure and function were evaluated by echocardiography and histological assessments. Gene expression in the heart was evaluated by RNA sequencing (RNA-seq), quantitative real-time RT-PCR (qRT-PCR), and Western blotting. Primary WT and Miat-KO mouse cardiomyocytes were isolated and used in Ca2+ transient and contractility measurements. Results: Continuous Ang II infusion for 4 weeks induced concentric hypertrophy in WT mice, but to a lesser extent in Miat-KO mice. Surgical TAC for 6 weeks resulted in decreased systolic function and heart failure in WT mice but not in Miat-KO mice. In both models, Miat-KO mice displayed reduced heart-weight to tibia-length ratio, cardiomyocyte cross-sectional area, cardiomyocyte apoptosis, and cardiac interstitial fibrosis and a better-preserved capillary density, as compared to WT mice. In addition, Ang II treatment led to significantly reduced mRNA and protein expression of the Ca2+ cycling genes Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) and ryanodine receptor 2 (RyR2) and a dramatic increase in global RNA splicing events in the left ventricle (LV) of WT mice, and these changes were largely blunted in Miat-KO mice. Consistently, cardiomyocytes isolated from Miat-KO mice demonstrated more efficient Ca2+ cycling and greater contractility. Conclusions: Ablation of Miat attenuates pathological hypertrophy and heart failure, in part, by enhancing cardiomyocyte contractility.


Assuntos
Insuficiência Cardíaca/genética , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/genética , Angiotensina II/farmacologia , Animais , Apoptose , Cardiomegalia/genética , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Masculino , Camundongos , Camundongos Knockout , Infarto do Miocárdio/patologia , RNA Longo não Codificante/metabolismo
5.
Am J Physiol Heart Circ Physiol ; 321(3): H496-H508, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34270373

RESUMO

Angiotensin II (ANG II) plays an important role in the regulation of various physiological functions including proliferation, hypertrophy of vascular smooth muscle cells (VSMCs) through the overexpression of Giα proteins. Sirtuin 1 (Sirt1), a class III histone deacetylase and epigenetic regulator is implicated in a wide range of cellular functions, including migration and growth of VSMCs and in ANG II-induced hypertension. The present study was undertaken to examine the role of Sirt1 in ANG II-induced overexpression of Giα proteins and hyperproliferation of aortic VSMCs. We show that ANG II treatment of VSMCs increased the expression of Sirt1, which was attenuated by AT1 and AT2 receptor antagonists, losartan, and PD123319, respectively. In addition, the knockdown of Sirt1 by siRNA attenuated ANG II-induced overexpression of Giα-2 and Giα-3 proteins, hyperproliferation of VSMCs and the overexpression of cell cycle proteins, cyclin D1, Cdk4, and phosphorylated retinoblastoma proteins. Furthermore, ANG II-induced increased levels of superoxide anion (O2-) and NADPH oxidase activity and increased phosphorylation of ERK1/2 and Akt that are implicated in enhanced expression of Giα proteins and hyperproliferation of VSMCs were also attenuated to control levels by silencing of Sirt1. In addition, depletion of Sirt1 by siRNA also attenuated ANG II-induced enhanced phosphorylation of platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), and insulin-like growth factor receptor (IGFR) in VSMCs. In summary, our results demonstrate that ANG II increased the expression of Sirt1, which through oxidative stress, growth factor receptor-mediated mitogen-activated protein (MAP) kinase/Akt signaling pathway enhances the expression of Giα proteins and cell cycle proteins and results in the hyperproliferation of VSMCs.NEW & NOTEWORTHY ANG II regulates various physiological functions including proliferation of VSMCs through the overexpression of Giα proteins. Sirt1, a class III histone deacetylase, is implicated in several cellular functions, including VSMC growth and ANG II-induced hypertension. We showed for the first time that ANG II increased the expression of Sirt1, which through oxidative stress, growth factor receptor-mediated MAP kinase/Akt signaling pathway enhances the levels of Giα and cell cycle proteins resulting in the hyperproliferation of VSMCs.


Assuntos
Angiotensina II/farmacologia , Proliferação de Células , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Sirtuína 1/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/citologia , Células Cultivadas , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Humanos , Imidazóis/farmacologia , Losartan/farmacologia , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Sirtuína 1/metabolismo
6.
Biomed Pharmacother ; 139: 111688, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243612

RESUMO

Cardiac hypertrophy is a current, major, global health challenge. Oxidative stress is an important mechanism that contributes to the pathogenesis of cardiac hypertrophy. Schisandra chinensis polysaccharides (SCP), the primary active constituent in Schisandra chinensis, have antioxidative properties. Here, we investigated the role played by SCP in a cardiac hypertrophy model mouse induced by transverse aortic constriction (TAC). We found that SCP treatment improved cardiac function by inhibiting myocardial hypertrophy and oxidative stress. Angiotensin II was used to induce cardiomyocyte hypertrophy and oxidative stress in vitro. We discovered that the antioxidant effects of SCP were mediated through the regulation of the thioredoxin-interacting protein (TXNIP)/Thioredoxin-1 (Trx-1) pathway. Using molecular docking, we found that SCP binds to Arg207, Ser169, Lys166, Lys286 and Ser285 in TXNIP through hydrogen bonds. TXNIP is an endogenous inhibitor of Trx-1, and the binding SCP with TXNIP may restrict or interfere with the binding between TXNIP and Trx-1, resulting in Trx-1 activation. In conclusion, our findings demonstrated that the potential use of SCP as a TXNIP inhibitor to attenuate oxidative stress, suggesting that TXNIP might represent a potential therapeutic target for the treatment of cardiac hypertrophy.


Assuntos
Cardiomegalia/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Schisandra/metabolismo , Tiorredoxinas/metabolismo , Angiotensina II/farmacologia , Animais , Antioxidantes/fisiologia , Cardiomegalia/metabolismo , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular/métodos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos
7.
Molecules ; 26(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069330

RESUMO

Angiotensin (Ang) II is well-known to have potent pro-oxidant and pro-inflammatory effects in the brain. Extensive crosstalk between the primary Ang II receptor, Ang type 1 receptor (AT1R), and the cannabinoid type 1 receptor (CB1R) has been demonstrated by various groups in the last decade. Since activation of glial CB1R has been demonstrated to play a key role in the resolution of inflammatory states, we investigated the role of Ang II (100 nM) and/or ACEA (10 nM), a potent CB1R-specific agonist in the regulation of inflammatory markers in astrocytes from spontaneously hypertensive rats (SHR) and Wistar rats. Astrocytes were cultured from brainstems and cerebellums of SHR and Wistar rats and assayed for IL1ß and IL10 gene expression and secreted fraction, in treated and non-treated cells, by employing qPCR and ELISA, respectively. mRNA expression of both IL10 and IL1ß were significantly elevated in untreated brainstem and cerebellar astrocytes isolated from SHR when compared to Wistar astrocytes. No changes were observed in the secreted fraction. While ACEA-treatment resulted in a significant increase in IL10 gene expression in Wistar brainstem astrocytes (Log2FC ≥ 1, p < 0.05), its effect in SHR brainstem astrocytes was diminished. Ang II treatment resulted in a strong inhibitory effect on IL10 gene expression in astrocytes from both brain regions of SHR and Wistar rats (Log2FC ≤ -1, p < 0.05), and an increase in IL1ß gene expression in brainstem astrocytes from both strains (Log2FC ≥ 1, p < 0.05). Co-treatment of Ang II and ACEA resulted in neutralization of Ang II-mediated effect in Wistar brainstem and cerebellar astrocytes, but not SHR astrocytes. Neither Ang II nor ACEA resulted in any significant changes in IL10 or IL1ß secreted proteins. These data suggest that Ang II and ACEA have opposing roles in the regulation of inflammatory gene signature in astrocytes isolated from SHR and Wistar rats. This however does not translate into changes in their secreted fractions.


Assuntos
Angiotensina II/farmacologia , Ácidos Araquidônicos/farmacologia , Expressão Gênica/efeitos dos fármacos , Interleucina-10/genética , Interleucina-18/genética , Animais , Astrócitos/efeitos dos fármacos , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Masculino , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
8.
Am J Physiol Heart Circ Physiol ; 321(2): H382-H389, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34142888

RESUMO

Pulmonary hypertension (PH) is associated with structural remodeling of pulmonary arteries (PAs) because of excessive proliferation of fibroblasts, endothelial cells, and smooth muscle cells (SMCs). The peptide hormone angiotensin II (ANG II) contributes to pulmonary vascular remodeling, in part, through its ability to trigger extracellular signal-regulated kinase (ERK1/2) activation. Here, we demonstrate that the ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5), functions as a negative regulator of ANG II-mediated SMC proliferation and PH. In contrast to wild-type controls, Dusp5 null mice infused with ANG II developed PH and right ventricular (RV) hypertrophy. PH in Dusp5 null mice was associated with thickening of the medial layer of small PAs, suggesting an in vivo role for DUSP5 as a negative regulator of ANG II-dependent SMC proliferation. Consistent with this, overexpression of DUSP5 blocked ANG II-mediated proliferation of cultured human pulmonary artery SMCs (hPASMCs) derived from patients with idiopathic PH or from failed donor controls. Collectively, the data support a role for DUSP5 as a feedback inhibitor of ANG II-mediated ERK signaling and PASMC proliferation and suggest that disruption of this circuit leads to adverse cardiopulmonary remodeling.NEW & NOTEWORTHY Dual-specificity phosphatases (DUSPs) serve critical roles in the regulation of mitogen-activated protein kinases, but their functions in the cardiovascular system remain poorly defined. Here, we provide evidence that DUSP5, which resides in the nucleus and specifically dephosphorylates extracellular signal-regulated kinase (ERK1/2), blocks pulmonary vascular smooth muscle cell proliferation. In response to angiotensin II infusion, mice lacking DUSP5 develop pulmonary hypertension and right ventricular cardiac hypertrophy. These findings illustrate DUSP5-mediated suppression of ERK signaling in the lungs as a protective mechanism.


Assuntos
Proliferação de Células/genética , Fosfatases de Especificidade Dupla/genética , Ventrículos do Coração/metabolismo , Hipertensão Pulmonar/genética , Hipertrofia Ventricular Direita/genética , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Remodelação Vascular/genética , Angiotensina II/farmacologia , Animais , Estudos de Casos e Controles , Células Cultivadas , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/fisiopatologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Vasoconstritores/farmacologia
9.
Am J Physiol Cell Physiol ; 321(1): C158-C175, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34038243

RESUMO

In whole cell patch clamp recordings, it was discovered that normal human adrenal zona glomerulosa (AZG) cells express members of the three major families of K+ channels. Among these are a two-pore (K2P) leak-type and a G protein-coupled, inwardly rectifying (GIRK) channel, both inhibited by peptide hormones that stimulate aldosterone secretion. The K2P current displayed properties identifying it as TREK-1 (KCNK2). This outwardly rectifying current was activated by arachidonic acid and inhibited by angiotensin II (ANG II), adrenocorticotrophic hormone (ACTH), and forskolin. The activation and inhibition of TREK-1 was coupled to AZG cell hyperpolarization and depolarization, respectively. A second K2P channel, TASK-1 (KCNK3), was expressed at a lower density in AZG cells. Human AZG cells also express inwardly rectifying K+ current(s) (KIR) that include quasi-instantaneous and time-dependent components. This is the first report demonstrating the presence of KIR in whole cell recordings from AZG cells of any species. The time-dependent current was selectively inhibited by ANG II, and ACTH, identifying it as a G protein-coupled (GIRK) channel, most likely KIR3.4 (KCNJ5). The quasi-instantaneous KIR current was not inhibited by ANG II or ACTH and may be a separate non-GIRK current. Finally, AZG cells express a voltage-gated, rapidly inactivating K+ current whose properties identified as KV1.4 (KCNA4), a conclusion confirmed by Northern blot. These findings demonstrate that human AZG cells express K2P and GIRK channels whose inhibition by ANG II and ACTH is likely coupled to depolarization-dependent secretion. They further demonstrate that human AZG K+ channels differ fundamentally from the widely adopted rodent models for human aldosterone secretion.


Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Angiotensina II/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Canal de Potássio Kv1.4/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Zona Glomerulosa/metabolismo , Adolescente , Adulto , Aldosterona/biossíntese , Ácido Araquidônico/farmacologia , Autopsia , Criança , Colforsina/farmacologia , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Expressão Gênica , Humanos , Canal de Potássio Kv1.4/antagonistas & inibidores , Canal de Potássio Kv1.4/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Técnicas de Patch-Clamp , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Cultura Primária de Células , Zona Glomerulosa/citologia , Zona Glomerulosa/efeitos dos fármacos
10.
Am J Physiol Renal Physiol ; 320(6): F1080-F1092, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33969697

RESUMO

A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT1) receptors in the kidney, stimulating Na+ reabsorption. AT1 receptors in tubular epithelia control expression and stimulation of Na+ transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT1 receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na+ excretion in SMKO mice, we considered whether alterations in Na+ transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na+ transporters and associated proteins. Here, we show that levels of Na+-K+-2Cl- cotransporter isoform 2 (NKCC2) and Na+/H+ exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser71), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na+ channel. However, the increases in α- and γ-epithelial Na+ channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na+ excretion observed after cell-specific deletion of AT1 receptors from smooth muscle cells is associated with altered Na+ transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na+ transporters and contributing to the regulation of pressure natriuresis.NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise mechanism for how these medications control blood pressure is incompletely understood. Here, we show that mice lacking angiotensin receptors specifically in smooth muscle cells lead to alternation in tubular transporter amount and function. Thus, demonstrating the importance of vascular-tubular cross talk in the control of blood pressure.


Assuntos
Angiotensina II/farmacologia , Células Epiteliais/metabolismo , Rim/irrigação sanguínea , Miócitos de Músculo Liso/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Amilorida/farmacologia , Animais , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Feminino , Furosemida/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde , Hipertensão/induzido quimicamente , Proteínas Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Receptor Tipo 1 de Angiotensina/genética , Sódio/metabolismo , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia
11.
Am J Physiol Renal Physiol ; 321(1): F69-F81, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34056928

RESUMO

The renal nephron consists of a series of distinct cell types that function in concert to maintain fluid and electrolyte balance and blood pressure. The renin-angiotensin system (RAS) is central to Na+ and volume balance. We aimed to determine how loss of angiotensin II signaling in the proximal tubule (PT), which reabsorbs the bulk of filtered Na+ and volume, impacts solute transport throughout the nephron. We hypothesized that PT renin-angiotensin system disruption would not only depress PT Na+ transporters but also impact downstream Na+ transporters. Using a mouse model in which the angiotensin type 1a receptor (AT1aR) is deleted specifically within the PT (AT1aR PTKO), we profiled the abundance of Na+ transporters, channels, and claudins along the nephron. Absence of PT AT1aR signaling was associated with lower abundance of PT transporters (Na+/H+ exchanger isoform 3, electrogenic Na+-bicarbonate cotransporter 1, and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated Na+-K+-2Cl- cotransporter, medullary Na+-K+-ATPase, phosphorylated NaCl cotransporter, and claudin 7) versus controls. However, transport activities of Na+-K+-2Cl- cotransporter and NaCl cotransporter (assessed with diuretics) were similar between groups in order to maintain electrolyte balance. Together, these results demonstrate the primary impact of angiotensin II regulation on Na+ reabsorption in the PT at baseline and the associated influence on downstream Na+ transporters, highlighting the ability of the nephron to integrate Na+ transport along the nephron to maintain homeostasis.NEW & NOTEWORTHY Our study defines a novel role for proximal tubule angiotensin receptors in regulating the abundance of Na+ transporters throughout the nephron, thereby contributing to the integrated control of fluid balance in vivo.


Assuntos
Angiotensina II/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Néfrons/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Animais , Rim/metabolismo , Natriurese/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio/metabolismo
12.
Am J Physiol Heart Circ Physiol ; 320(6): H2416-H2428, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33989083

RESUMO

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. We characterized eNOS null and wild-type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, eight groups of mice were divided into four groups of eNOS null mice and WT mice; half of the mice received angiotensin II (ANG II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, ANG II administration not only increased cardiac fibrosis but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.NEW & NOTEWORTHY ECs compensate for eNOS deficiency by increasing the secretion of NRG1. NRG1 administration prevents cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. NRG1 expression is regulated by miR-134.


Assuntos
Células Endoteliais/metabolismo , Frequência Cardíaca/genética , Coração/efeitos dos fármacos , MicroRNAs/metabolismo , Miocárdio/patologia , Neuregulina-1/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico/metabolismo , Angiotensina II/farmacologia , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Diástole/efeitos dos fármacos , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica , Frequência Cardíaca/efeitos dos fármacos , Rim/patologia , Camundongos , Camundongos Knockout , Neuregulina-1/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Distribuição Aleatória , Vasoconstritores/farmacologia
13.
Biomed Pharmacother ; 140: 111689, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34004510

RESUMO

Vascular smooth muscle cell (VSMC) phenotypic switch plays an essential role in the pathogenesis of hypertension. Mitochondrial dynamics, such as mitochondrial fission, can also contribute to VSMC phenotypic switch. Whether mitochondrial fission act as a novel target for anti-hypertensive drug development remains unknown. In the present study, we confirmed that angiotensin II (AngII) rapidly and continuously induced mitochondrial fission in VSMCs. We also detected the phosphorylation status of dynamin-related protein-1 (Drp1), a key protein involved in mitochondrial fission, at Ser616 site; and observed Drp1 mitochondrial translocation in VSMCs or arteries of AngII-induced hypertensive mice. The Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) dramatically reversed AngII-induced Drp1 phosphorylation, mitochondrial fission, and reactive oxidative species generation. Treatment with Mdivi-1 (20 mg/kg/every other day) significantly attenuated AngII-induced hypertension (22 mmHg), arterial remodeling, and cardiac hypertrophy, in part by preventing VSMC phenotypic switch. In addition, Mdivi-1 treatment was not associated with liver or renal functional injury. Collectively, these results indicate that Mdivi-1 inhibited mitochondrial fission, recovered mitochondrial activity, and prevented AngII-induced VSMC phenotypic switch, resulting in reduced hypertension.


Assuntos
Angiotensina II/farmacologia , Hipertensão/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Quinazolinonas/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Células Cultivadas , Dinaminas/metabolismo , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
14.
Cell Biochem Funct ; 39(5): 688-698, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33821520

RESUMO

The meninges shield the nervous system from diverse, rather harmful stimuli and pathogens from the periphery. This tissue is composed of brain endothelial cells (BECs) that express diverse ion channels and chemical-transmitter receptors also expressed by neurons and glial cells to communicate with each other. However, information about the effects of ATP and angiotensin II on BECs is scarce, despite their essential roles in blood physiology. This work investigated in vitro if BECs from the meninges from rat forebrain respond to ATP, angiotensin II and high extracellular potassium, with intracellular calcium mobilizations and its second messenger-associated pathways. We found that in primary BEC cultures, both ATP and angiotensin II produced intracellular calcium responses linked to the activation of inositol trisphosphate receptors and ryanodine receptors, which led to calcium release from intracellular stores. We also used RT-PCR to explore what potassium channel subunits are expressed by primary BEC cultures and freshly isolated meningeal tissue, and which might be linked to the observed effects. We found that BECs mainly expressed the inward rectifier potassium channel subunits Kir1.1, Kir3.3, Kir 4.1 and Kir6.2. This study contributes to the understanding of the functions elicited by ATP and angiotensin II in BECs from rat meninges. SIGNIFICANCE OF THE STUDY: Brain endothelial cells (BECs) express diverse ion channels and membrane receptors, which they might use to communicate with neurons and glia. This work investigated in vitro, if BECs from the rat forebrain respond to angiotensin II and ATP with intracellular calcium mobilizations. We found that these cells did respond to said substances with intracellular calcium mobilizations linked to inositol trisphosphate and ryanodine receptor activation, which led to calcium release from intracellular stores. These findings are important because they might uncover routes of active communication between brain cells and endothelial cells.


Assuntos
Trifosfato de Adenosina/farmacologia , Angiotensina II/farmacologia , Cálcio/metabolismo , Células Endoteliais/efeitos dos fármacos , Potássio/farmacologia , Prosencéfalo/metabolismo , Animais , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Masculino , Canais de Potássio/genética , Canais de Potássio/metabolismo , Prosencéfalo/efeitos dos fármacos , Ratos , Ratos Wistar
15.
Biochem Biophys Res Commun ; 557: 77-84, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33862463

RESUMO

4-octyl itaconate (OI) is one kind of cell-permeable derivative of itaconate to regulate inflammation and oxidative stress. However, its effects on the angiotensin II (Ang II)-induced inflammatory response and oxidative stress in human primary retinal pigment epithelium (hRPE) cells as well as its underlying mechanisms were unclear. In this study, we found that OI suppressed changes in pro-inflammatory cytokines (MCP-1, IL-8, and IL-6) and reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) via activation of Nrf2 signaling in Ang II-treated hRPE cells. A total of 645 differentially expressed long non-coding RNAs (lncRNAs) and 455 mRNAs were identified by microarray analysis. Ten lncRNAs were analyzed using the Coding-non-coding gene co-expression (CNC) network and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, revealing that many differentially expressed lncRNAs were enriched in immune response-related pathways, such as IL-17, TNF, and NOD-like receptor signaling. This finding suggested that OI inhibits Ang II-induced inflammatory response and oxidative stress by activating Nrf2 signaling in hRPE cells. We also provided a novel perspective on the role of lncRNAs in the protective effects of OI.


Assuntos
Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Succinatos/farmacologia , Angiotensina II/farmacologia , Citocinas/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Estresse Oxidativo/fisiologia , Cultura Primária de Células , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Epitélio Pigmentado da Retina/patologia , Transdução de Sinais , Vasoconstritores/farmacologia
16.
Mol Pharmacol ; 99(6): 469-487, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33795351

RESUMO

Angiotensin II (Ang II) is the most dominant effector component of the renin-angiotensin system (RAS) that generally acts through binding to two main classes of G protein-coupled receptors, namely Ang II subtype 1 receptor (AT1R) and angiotensin II subtype 2 receptor (AT2R). Despite some controversial reports, the activation of AT2R generally antagonizes the effects of Ang II binding on AT1R. Studying AT2R signaling, function, and its specific ligands in cell culture or animal studies has confirmed its beneficial effects throughout the body. These characteristics classify AT2R as part of the protective arm of the RAS that, along with functions of Ang (1-7) through Mas receptor signaling, modulates the harmful effects of Ang II on AT1R in the activated classic arm of the RAS. Although Ang II is the primary ligand for AT2R, we have summarized other natural or synthetic peptide and nonpeptide agonists with critical evaluation of their structure, mechanism of action, and biologic activity. SIGNIFICANCE STATEMENT: AT2R is one of the main components of the RAS and has a significant prospective for mediating the beneficial action of the RAS through its protective arm on the body's homeostasis. Targeting AT2R offers substantial clinical application possibilities for modulating various pathological conditions. This review provided concise information regarding the AT2R peptide and nonpeptide agonists and their potential clinical applications for various diseases.


Assuntos
Peptídeos/farmacologia , Receptor Tipo 2 de Angiotensina/agonistas , Angiotensina II/química , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Humanos , Ligantes , Peptídeos/química , Conformação Proteica , Receptor Tipo 2 de Angiotensina/química , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais , Relação Estrutura-Atividade
17.
J Biochem Mol Toxicol ; 35(7): e22789, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33847027

RESUMO

Previously, we established several facts regarding hypertension-associated cataractogenesis. As a follow-on study, we evaluated the role of the renin-angiotensin system (RAS) in angiotensin-II (Ang-II)-induced cataract formation in experimental hypertensive rats. Sprague-Dawley male albino rats (150-180 g) were used for the present experiment. The animals were divided into four groups, with six animals in each group. During the 12 weeks of the experimental protocol, the normal group received sterile water (1 ml/kg/day, subcutaneously (sc), and the Ang-II control group received angiotensin (1 mg/kg/day) subcutaneously. The ARB (O) group received olmesartan (2 mg/kg/day) orally, and the ARB (T) group received two drops of olmesartan (5 mM) topically on the cornea; concurrently, both groups were treated with Ang-II (1 mg/kg/day, sc) to induce hypertension. Biweekly, the systolic and the diastolic blood pressures were recorded, and the eyes were examined; moreover, cataractogenic parameters, such as oxidative stress markers and protein contents in the lenses, were evaluated after completion of the experimental protocol. Twelve weeks of olmesartan administered, orally or topically, significantly reduced the progression of cataract formation and restored antioxidants, lipid peroxidation, nitrite content, and protein contents in the lenses of the mice in groups O and T, respectively, as compared with those in the Ang-II control group. On the basis of our results, we conclude that the ocular RAS exacerbates the lenticular oxidative stress that may lead to cataract formation. The results showed that the RAS has an independent and important role in cataract formation under hypertensive conditions.


Assuntos
Angiotensina II/efeitos adversos , Catarata , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Catarata/induzido quimicamente , Catarata/metabolismo , Catarata/patologia , Imidazóis/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Tetrazóis/farmacologia
18.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801629

RESUMO

The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and ß1 protein content remained unchanged, and the cardiac Na/K-ATPase dose-response curve to ouabain shifted to the left as expected. In males aged 3-6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1r/rα2s/s mouse failed to do so in the α1s/sα2s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.


Assuntos
Glicosídeos Cardíacos/química , Coração/fisiologia , Miocárdio/enzimologia , ATPase Trocadora de Sódio-Potássio/genética , Angiotensina II/farmacologia , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Ecocardiografia , Coração/efeitos dos fármacos , Masculino , Camundongos , Mutação , Ouabaína/farmacologia , Isoformas de Proteínas , RNA-Seq , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos
19.
Clin Sci (Lond) ; 135(7): 943-961, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33822013

RESUMO

Clinical trials indicate that sodium/glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, n=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) mRNA levels (P<0.001). In vitro, angiotensin II (Ang II) dose-dependently stimulated SGLT2 expression in HK-2, human immortalized renal proximal tubular cells (RPTCs); losartan and antioxidants inhibited it. Sglt2 expression was increased in transgenic (Tg) mice specifically overexpressing Agt in their RPTCs, as well as in WT mice with a single subcutaneous injection of Ang II (1.44 mg/kg). Moreover, Ang II (1000 ng/kg/min) infusion via osmotic mini-pump in WT mice for 4 weeks increased systolic blood pressure (SBP), glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria; canaglifozin (Cana, 15 mg/kg/day) reversed these changes, with the exception of SBP. Fractional glucose excretion (FeGlu) was higher in Ang II+Cana than WT+Cana, whereas Sglt2 expression was similar. Our data demonstrate a link between intrarenal RAS and SGLT2 expression and that SGLT2i ameliorates Ang II-induced renal injury independent of SBP.


Assuntos
Angiotensina II/farmacologia , Nefropatias/fisiopatologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Adulto , Animais , Linhagem Celular , Feminino , Humanos , Hipertensão/induzido quimicamente , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/genética
20.
Chem Biol Interact ; 342: 109475, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33872574

RESUMO

Endorphins are endogenous opioid neuropeptides that are mainly produced from pituitary gland in response to pain and different triggers including interleukin 1 beta (IL-1ß) and corticotropin-releasing factor (CRF). Angiotensin II (Ang II) can stimulate ß-endorphin production, but the exact molecular mechanisms involved in this effect, and the role of the released ß-endorphin in Ang II-mediated pressor response remain elusive. Male rats were injected with IL-1ß receptor antagonist (IL-1Ra, 100 µg/kg), the CRF receptor blocker, astressin (20 µg/rat) or a combination of both, prior to Ang II injection (200 µg/kg). Another group of rats was given naloxone (1.6 mg/kg) or telmisartan (5 mg/kg) before Ang II injection. Blood pressure and serum and Paraventricular nucleus (PVN) ß-endorphin were detected. Moreover, IL-1ß and CRF as well as markers of oxidative stress [malondialdehyde (MDA) and superoxide dismutase (SOD)], inflammation [C-reactive protein (CRP)] and neuronal activation (c-Fos, l-glutamate, and phosphorylated ERK) were measured in the PVN of different groups. Ang II induced a pressor response and increased serum and PVN ß-endorphin levels that were attenuated in rats pre-treated with astressin or/and IL-1Ra. Moreover, Ang II increased PVN oxidative stress, inflammation and neuronal activation. Telmisartan abolished the previous effects, while naloxone, astressin and IL-1Ra aggravated Ang II-mediated pressor response and most of the biochemical changes. These findings suggest that, Ang II can induce ß-endorphin release via increasing both IL-1ß and CRF levels which in result mitigates Ang II-mediated central responses. This study highlights ß-endorphin as a possible target for treating hypertension.


Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , beta-Endorfina/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/metabolismo , Masculino , Naloxona/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Telmisartan/farmacologia
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