Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage

2011 ◽  
Vol 301 (1) ◽  
pp. E132-E144 ◽  
Author(s):  
Junling Yang ◽  
Yi Tan ◽  
Fenglian Zhao ◽  
Zhongsen Ma ◽  
Yuehui Wang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Lung Fibrosis ◽  
Critical Role ◽  
Receptor Expression ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Ang Ii ◽  
Diabetic Mice

Diabetic patients have a high risk of pulmonary disorders that are usually associated with restrictive impairment of lung function, suggesting a fibrotic process (van den Borst B, Gosker HR, Zeegers MP, Schols AM. Chest 138: 393–406, 2010; Ehrlich SF, Quesenberry CP Jr, Van Den Eeden SK, Shan J, Ferrara A. Diabetes Care 33: 55–60, 2010). The present study was undertaken to define whether and how diabetes causes lung fibrosis. Lung samples from streptozotocin-induced type 1 diabetic mice, spontaneously developed type 1 diabetic OVE26 mice, and their age-matched controls were investigated with histopathological and biochemical analysis. Signaling mechanism was investigated with cultured normal human lung fibroblasts in vitro. In both diabetes models, histological examination with Sirius red and hemotoxylin and eosin stains showed fibrosis along with massive inflammatory cell infiltration. The fibrotic and inflammatory processes were confirmed by real-time PCR and Western blotting assays for the increased fibronectin, CTGF, PAI-1, and TNFα mRNA and protein expressions. Diabetes also significantly increased NADPH oxidase (NOX) expression and protein nitration along with upregulation of angiotensin II (Ang II) and its receptor expression. In cell culture, exposure of lung fibroblasts to Ang II increased CTGF expression in a dose- and time-dependent manner, which could be abolished by inhibition of superoxide, NO, and peroxynitrite accumulation. Furthermore, chronic infusion of Ang II to normal mice at a subpressor dose induced diabetes-like lung fibrosis, and Ang II receptor AT1 blocker (losartan) abolished the lung fibrotic and inflammatory responses in diabetic mice. These results suggest that Ang II plays a critical role in diabetic lung fibrosis, which is most likely caused by NOX activation-mediated nitrosative damage.

scholarly journals Angiotensin II type 1 receptor blocker attenuates the activation of ERK and NADPH oxidase by mechanical strain in mesangial cells in the absence of angiotensin II

2009 ◽  
Vol 296 (5) ◽  
pp. F1052-F1060 ◽  
Author(s):  
Junichi Yatabe ◽  
Hironobu Sanada ◽  
Midori Sasaki Yatabe ◽  
Shigeatsu Hashimoto ◽  
Minoru Yoneda ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mesangial Cells ◽  
Mechanical Strain ◽  
Dependent Manner ◽  
Ang Ii ◽  
Erk Phosphorylation ◽  
Extracellular Signal

It has been reported that mechanical strain activates extracellular signal-regulated protein kinases (ERK) without the involvement of angiotensin II (Ang II) in cardiomyocytes. We examined the effects of mechanical strain on ERK phosphorylation levels in the absence of Ang II using rat mesangial cells. The ratio of phosphorylated ERK (p-ERK) to total ERK expression was increased by cyclic mechanical strain in a time- and elongation strength-dependent manner. With olmesartan [Ang II type 1 receptor (AT1R) antagonist] pretreatment, p-ERK plateau levels decreased in a dose-dependent manner (EC50 = 1.3 × 10−8 M, maximal inhibition 50.6 ± 11.0% at 10−5 M); a similar effect was observed with RNA interference against Ang II type 1A receptor (AT1AR) and Tempol, a superoxide dismutase mimetic. In addition to the inhibition of p-ERK levels, olmesartan blocked the increase in cell surface and phosphorylated p47phox induced by mechanical strain and also lowered the mRNA expression levels of NADPH oxidase subunits. These results demonstrate that mechanical strain stimulates AT1R to phosphorylate ERK in mesangial cells in the absence of Ang II. This mechanotransduction mechanism is involved in the oxidative stress caused by NADPH oxidase and is blocked by olmesartan. The inverse agonistic activity of this AT1R blocker may be useful for the prevention of mesangial proliferation and renal damage caused by mechanical strain/oxidative stress regardless of circulating or tissue Ang II levels.

scholarly journals Enhanced hemodynamic responses to angiotensin II in diabetes are associated with increased expression and activity of AT1 receptors in the afferent arteriole

2017 ◽  
Vol 49 (10) ◽  
pp. 531-540 ◽  
Author(s):  
Jie Zhang ◽  
Helena Y. Qu ◽  
Jiangping Song ◽  
Jin Wei ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mrna Level ◽  
At1 Receptor ◽  
Receptor Expression ◽  
Ang Ii ◽  
Diabetic Mice ◽  
At1 Receptors ◽  
Enhanced Expression ◽  
Bolus Intravenous Injection

The prevalence of hypertension is about twofold higher in diabetic than in nondiabetic subjects. Hypertension aggravates the progression of diabetic complications, especially diabetic nephropathy. However, the mechanisms for the development of hypertension in diabetes have not been elucidated. We hypothesized that enhanced constrictive responsiveness of renal afferent arterioles (Af-Art) to angiotensin II (ANG II) mediated by ANG II type 1 (AT1) receptors contributes to the development of hypertension in diabetes. In response to an acute bolus intravenous injection of ANG II, alloxan-induced diabetic mice exhibited a higher mean arterial pressure (MAP) (119.1 ± 3.8 vs. 106.2 ± 3.5 mmHg) and a lower renal blood flow (0.25 ± 0.07 vs. 0.52 ± 0.14 ml/min) compared with nondiabetic mice. In response to chronic ANG II infusion, the MAP measured with telemetry increased by 55.8 ± 6.5 mmHg in diabetic mice, but only by 32.3 ± 3.8 mmHg in nondiabetic mice. The mRNA level of AT1 receptor increased by ~10-fold in isolated Af-Art of diabetic mice compared with nondiabetic mice, whereas ANG II type 2 (AT2) receptor expression did not change. The ANG II dose-response curve of the Af-Art was significantly enhanced in diabetic mice. Moreover, the AT1 receptor antagonist, losartan, blocked the ANG II-induced vasoconstriction in both diabetic mice and nondiabetic mice. In conclusion, we found enhanced expression of the AT1 receptor and exaggerated response to ANG II of the Af-Art in diabetes, which may contribute to the increased prevalence of hypertension in diabetes.

Reactive Oxygen Species-Mediated Homologous Downregulation of Angiotensin II Type 1 Receptor Mrna by Angiotensin II

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Toshihiro Ichiki ◽  
Kotaro Takeda ◽  
Akira Takeshita
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mrna Expression ◽  
Crucial Role ◽  
Oxygen Species ◽  
Ang Ii ◽  
Stimulation Of

58 Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of Angiotensin II (Ang II) through type 1 Ang II receptor (AT1-R). However, the role of ROS in the regulation of AT1-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT1-R by Ang II. Ang II (10 -6 mol/L) decreased AT1-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells (VSMC). Ang II dose-dependently (10 -8 -10 -6 ) suppressed AT1-R mRNA at 6 hours of stimulation. Preincubation of VSMC with N-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT1-R mRNA. The effect of NAC was due to stabilization of the AT1-R mRNA that was destabilized by Ang II. Ang II did not affect the promoter activity of AT1-R gene. Diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase failed to inhibit the Ang II-induced AT1-R mRNA downregulation. The Ang II-induced AT1-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as PD98059 whereas DPI did not inhibit it. To confirm the role of ROS in the regulation of AT1-R mRNA expression, VSMC were stimulated with H 2 O 2 . H 2 O 2 suppressed the AT1-R mRNA expression and activated ERK. These results suggest that production of ROS and activation of ERK are critical for downregulation of AT1-R mRNA. The differential effect of NAC and DPI on the downregulation of AT1-R mRNA may suggest the presence of other sources than NADH/NADPH oxidase pathway for ROS in Ang II signaling. Generation of ROS through stimulation of AT1-R not only mediates signaling of Ang II but may play a crucial role in the adaptation process of AT1-R to the sustained stimulation of Ang II.

scholarly journals Angiotensin II Suppresses Rev-erbα Expression in THP-1 Macrophages via the Ang II Type 1 Receptor/Liver X Receptor α Pathway

2018 ◽  
Vol 46 (1) ◽  
pp. 303-313 ◽  
Author(s):  
Shipeng Wang ◽  
Xia Gu ◽  
Qi Zhang ◽  
Xiling Zhang ◽  
Yilan Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Atherosclerotic Lesion ◽  
Liver X Receptor ◽  
Time Dependent ◽  
Dependent Manner ◽  
Ang Ii ◽  
Raw264.7 Macrophages ◽  
Liver X Receptor Α

Background/Aims: Angiotensin II (Ang II) regulates the expression of some core clock genes; excess Ang II leads to atherosclerosis advancement. Macrophage Rev-erbα mediates clockwork and inflammation, and plays a role in atherosclerotic lesion progression. However, the role of Ang II in regulating Rev-erbα expression in macrophages remains unclarified. Methods: We induced THP-1 macrophages by phorbol 12-myristate 13-acetate and investigated the effect of Ang II on Rev-erbα expression via real-time polymerase chain reaction, western blotting and small interfering RNA (siRNA) techniques. The cytotoxicity of the Rev-erbα agonist SR9009 was analyzed using a (3-[4,5-dimethylthiazol-2-yl])-2,5- diphenyltetrazolium bromide assay. Results: Ang II suppressed Rev-erbα mRNA and protein expression in THP-1 macrophages in a dose and time dependent manner. This effect was mediated via Ang II type 1 receptor (AT1R), and not Ang II type 2 receptor or peroxisome proliferator-activated receptor γ (PPARγ). Consistent with Rev-erbα expression regulated by Ang II, the liver X receptor α (LXRα) protein expression was downregulated in a time-dependent manner after Ang II treatment. The activation or silence of LXRα significantly increased or decreased Rev-erbα expression regulated by Ang II, respectively. This suggests that LXRα is involved in the effect of Ang II on Rev-erbα expression. MMP-9 mRNA expressions were significantly suppressed by SR9009 in THP-1 and RAW264.7 macrophages; moreover, SR9009-treatment significantly reduced Ang II–induced MMP-9 protein expressions in two types of macrophages. Conclusion: Ang II downregulates Rev-erbα expression in THP-1 macrophages via the AT1R/LXRα pathway.

Angiotensin II and the fibroproliferative response to acute lung injury

2004 ◽  
Vol 286 (1) ◽  
pp. L156-L164 ◽  
Author(s):  
Richard P. Marshall ◽  
Peter Gohlke ◽  
Rachel C. Chambers ◽  
David C. Howell ◽  
Steve E. Bottoms ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Angiotensin Ii ◽  
Lung Injury ◽  
Ace Inhibitors ◽  
Transforming Growth Factor ◽  
Lung Fibroblasts ◽  
Collagen Deposition ◽  
Ang Ii ◽  
Potent Inducer

Angiotensin II (ANG II), generated by activation of local renin-angiotensin systems, is believed to play an important role in tissue repair and remodeling, in part via transforming growth factor-β (TGF-β). Angiotensin-converting enzyme (ACE) inhibitors have been shown to abrogate experimental lung injury via a number of potential mechanisms; however, the potentially fibroproliferative role for ANG II in the lung has not been characterized. We hypothesized that, after lung injury, ANG II would stimulate fibroblast procollagen synthesis and promote lung collagen deposition in rats. In vitro, ANG II was a potent inducer of procollagen production in human lung fibroblasts via activation of the type 1 receptor and, at least in part, via the autocrine action of TGF-β. After bleomycin-induced lung injury, an increase in lung ANG II concentration was observed by day 3 that preceded increases in lung collagen and was maintained until death at day 21. Administration of an ACE inhibitor (ramipril) reduced ACE activity, ANG II concentration, TGF-β expression, and collagen deposition. Losartan (an ANG II type 1 receptor antagonist) also attenuated the increase in TGF-β expression and lung collagen deposition. These observations suggest that ANG II, possibly generated locally within the lung, may play an important role in the fibrotic response to acute lung injury, at least in part via the action of TGF-β. ACE inhibitors and receptor antagonists, already widely used clinically, should be assessed as potential new therapies for fibrotic lung disease.

scholarly journals mTORC1 Signaling Contributes to Drinking But Not Blood Pressure Responses to Brain Angiotensin II

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3140-3148 ◽  
Author(s):  
Kenjiro Muta ◽  
Donald A. Morgan ◽  
Justin L. Grobe ◽  
Curt D. Sigmund ◽  
Kamal Rahmouni
Keyword(s):  
Angiotensin Ii ◽  
Water Intake ◽  
Drinking Behavior ◽  
Subfornical Organ ◽  
Dependent Manner ◽  
Ang Ii ◽  
Mtorc1 Signaling ◽  
Wide Range ◽  
The Brain

Mechanistic target of rapamycin complex 1 (mTORC1) is a molecular node that couples extracellular cues to a wide range of cellular events controlling various physiological processes. Here, we identified mTORC1 signaling as a critical mediator of angiotensin II (Ang II) action in the brain. In neuronal GT1–7 cells, we show that Ang II stimulates neuronal mTORC1 signaling in an Ang II type 1 receptor-dependent manner. In mice, a single intracerebroventricular (ICV) injection or chronic sc infusion of Ang II activated mTORC1 signaling in the subfornical organ, a critical brain region in cardiovascular control and fluid balance. Moreover, transgenic sRA mice with brain-specific overproduction of Ang II displayed increased mTORC1 signaling in the subfornical organ. To test the functional role of brain mTORC1 in mediating the action of Ang II, we examined the consequence of mTORC1 inhibition with rapamycin on Ang II-induced increase in water intake and arterial pressure. ICV pretreatment with rapamycin blocked ICV Ang II-mediated increases in the frequency, duration, and amount of water intake but did not interfere with the pressor response evoked by Ang II. In addition, ICV delivery of rapamycin significantly reduced polydipsia, but not hypertension, of sRA mice. These results demonstrate that mTORC1 is a novel downstream pathway of Ang II type 1 receptor signaling in the brain and selectively mediates the effect of Ang II on drinking behavior.

scholarly journals α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions

2021 ◽  
Vol 8 ◽  
Author(s):  
Aarón Guerrero ◽  
Bruna Visniauskas ◽  
Pilar Cárdenas ◽  
Stefanny M. Figueroa ◽  
Jorge Vivanco ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Angiotensin Ii ◽  
High Glucose ◽  
In Silico ◽  
Apical Membrane ◽  
Collecting Duct ◽  
Receptor Expression ◽  
Ang Ii ◽  
Diabetic Mice ◽  
Intracellular Ca

Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na+ handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na+ reabsorption. In DM, the Kreb's cycle is in a state of suppression in most tissues. However, in the CD, expression of glucose transporters is augmented, boosting the Kreb's cycle and consequently causing α-ketoglutarate (αKG) accumulation. The αKG receptor 1 (OXGR1) is a Gq-coupled receptor expressed on the apical membrane of IC cells of the CD. We hypothesize that HG causes αKG secretion and activation of OXGR1, which increases PRR expression in CD cells. This effect then promotes intratubular AngII formation and Na+ reabsorption. To test this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with or without montelukast (ML), an OXGR1 antagonist, for 6 days. STZ mice had higher urinary αKG and PRR expression along with augmented urinary AngII levels and Na+ retention. Treatment with ML prevented all these effects. Similarly, primary cultured inner medullary CD cells treated with HG showed increased PRR expression, while OXGR1 antagonist prevented this effect. αKG increases PRR expression, while treatments with ML, PKC inhibition, or intracellular Ca2+ depletion impair this effect. In silico analysis suggested that αKG binds to mouse OXGR1. These results indicate that HG conditions promote increased levels of intratubular αKG and OXGR1-dependent PRR upregulation, which impact AngII formation and Na+ reabsorption.

Localization of Angiotensin II Type 1 receptor gene expression in rodent and human kidneys

2021 ◽  
Author(s):  
Julia Schrankl ◽  
Michaela Fuchs ◽  
Katharina Broeker ◽  
Christoph Daniel ◽  
Armin Kurtz ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mesangial Cells ◽  
Vascular System ◽  
Receptor Gene ◽  
Cell Types ◽  
Receptor Expression ◽  
Ang Ii ◽  
Comprehensive Overview ◽  
Different Cell Types

The kidneys are an important target for angiotensin II (ANG II). In the adult kidneys the effects of ANG II are mediated mainly by ANG II type 1 (AT1) receptors. AT1 receptor expression has been reported for a variety of different cell types within the kidneys, suggesting a broad spectrum of actions for ANG II. Since there have been heterogeneous results in the literature regarding the intrarenal distribution of AT1 receptors, this study aimed to obtain a comprehensive overview about the localization of AT1 receptor expression in mouse, rat and human kidneys. Using the cell specific and high-resolution RNAscope technique, we performed colocalization studies with various cell markers to specifically discriminate between different segments of the tubular and vascular system. Overall we found a similar pattern of AT1 mRNA expression in mouse, rat and human kidneys. AT1 receptors were detected in mesangial cells and renin-producing cells. In addition, AT1 mRNA was found in interstitial cells of the cortex and outer medulla. In rodents, late afferent and early efferent arterioles expressed AT1 receptor mRNA, but larger vessels of the investigated species showed no AT1 expression. Tubular expression of AT1 mRNA was species-dependent with a strong expression in proximal tubules of mice while expression was undetectable in human tubular cells. These findings suggest that the (juxta)glomerular area and the tubulointerstitium are conserved expression sites for AT1 receptors across species and might present the main target sites for ANG II in adult human and rodent kidneys.

scholarly journals Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome

2018 ◽  
Vol 45 (4) ◽  
pp. 1366-1376 ◽  
Author(s):  
Xian-Yun Qin ◽  
Yun-Long Zhang ◽  
Ya-Fei Chi ◽  
Bo Yan ◽  
Xiang-Jun Zeng ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Angiotensin Ii ◽  
Ubiquitin Proteasome System ◽  
Jurkat Cells ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Ang Ii ◽  
Th1 Cell

Background/Aims: Naive CD4+ T cells differentiate into T helper cells (Th1 and Th2) that play an essential role in the cardiovascular diseases. However, the molecular mechanism by which angiotensin II (Ang II) promotes Th1 differentiation remains unclear. The aim of this study was to determine whether the Ang II-induced Th1 differentiation regulated by ubiquitin-proteasome system (UPS). Methods: Jurkat cells were treated with Ang II (100 nM) in the presence or absence of different inhibitors. The gene mRNA levels were detected by real-time quantitative PCR analysis. The protein levels were measured by ELISA assay or Western blot analysis, respectively. Results: Ang II treatment significantly induced a shift from Th0 to Th1 cell differentiation, which was markedly blocked by angiotensin II type 1 receptor (AT1R) inhibitor Losartan (LST). Moreover, Ang II significantly increased the activities and the expression of proteasome catalytic subunits (β1, β1i, β2i and β5i) in a dose- and time-dependent manner. However, Ang II-induced proteasome activities were remarkably abrogated by LST and PKA inhibitor H-89. Mechanistically, Ang II-induced Th1 differentiation was at least in part through proteasome-mediated degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB. Conclusions: This study for the first time demonstrates that Ang II activates AT1R-PKA-proteasome pathway, which promotes degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB thereby leading to Th1 differentiation. Thus, inhibition of proteasome activation might be a potential therapeutic target for Th1-mediated diseases.

scholarly journals Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase

2014 ◽  
Vol 307 (7) ◽  
pp. C634-C647 ◽  
Author(s):  
Anna Cozzoli ◽  
Antonella Liantonio ◽  
Elena Conte ◽  
Maria Cannone ◽  
Ada Maria Massari ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Calcium Homeostasis ◽  
Potassium Conductance ◽  
Mdx Mouse ◽  
Dependent Manner ◽  
Ang Ii ◽  
Concentration Dependent Manner

Angiotensin II (ANG II) plays a role in muscle wasting and remodeling; however, little evidence shows its direct effects on specific muscle functions. We presently investigated the acute in vitro effects of ANG II on resting ionic conductance and calcium homeostasis of mouse extensor digitorum longus (EDL) muscle fibers, based on previous findings that in vivo inhibition of ANG II counteracts the impairment of macroscopic ClC-1 chloride channel conductance (gCl) in the mdx mouse model of muscular dystrophy. By means of intracellular microelectrode recordings we found that ANG II reduced gCl in the nanomolar range and in a concentration-dependent manner (EC50 = 0.06 μM) meanwhile increasing potassium conductance (gK). Both effects were inhibited by the ANG II receptors type 1 (AT1)-receptor antagonist losartan and the protein kinase C inhibitor chelerythrine; no antagonism was observed with the AT2 antagonist PD123,319. The scavenger of reactive oxygen species (ROS) N-acetyl cysteine and the NADPH-oxidase (NOX) inhibitor apocynin also antagonized ANG II effects on resting ionic conductances; the ANG II-dependent gK increase was blocked by iberiotoxin, an inhibitor of calcium-activated potassium channels. ANG II also lowered the threshold for myofiber and muscle contraction. Both ANG II and the AT1 agonist L162,313 increased the intracellular calcium transients, measured by fura-2, with a two-step pattern. These latter effects were not observed in the presence of losartan and of the phospholipase C inhibitor U73122 and the in absence of extracellular calcium, disclosing a Gq-mediated calcium entry mechanism. The data show for the first time that the AT1-mediated ANG II pathway, also involving NOX and ROS, directly modulates ion channels and calcium homeostasis in adult myofibers.

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