Angiotensinogen's role in ANG formation, renin release, and renal hemodynamics in isolated perfused kidney

1989 ◽  
Vol 256 (4) ◽  
pp. F719-F727 ◽  
Author(s):  
J. Misumi ◽  
J. Gardes ◽  
M. F. Gonzalez ◽  
P. Corvol ◽  
J. Menard
Keyword(s):  
Perfusion Pressure ◽  
Renin Angiotensin System ◽  
Renal Hemodynamics ◽  
Renin Release ◽  
Ang Ii ◽  
Angiotensin I ◽  
Angiotensin System ◽  
Perfusate Flow ◽  
Free Plasma

Isolated perfused rat kidneys were used to investigate the effects of the addition of pure angiotensinogen or renin-free plasma to the perfusate on angiotensin I (ANG I) and angiotensin II (ANG II) generation, renal hemodynamics, and renin release. When no angiotensinogen or plasma is added, a very small amount of angiotensinogen is initially detected in the perfusate. Whereas renin secreted by the kidney accumulates in the perfusate, angiotensinogen disappears during the perfusion and immunoreactive ANG II cannot be detected. The addition of angiotensinogen reactivates the renin-angiotensin system. ANG I, [des-Asp1] ANG I, ANG II, and [des-Asp1] ANG II are progressively generated in the perfusate. At a constant perfusion pressure, as well as at a variable perfusion pressure, a progressive fall in renal perfusate flow is observed that is significantly correlated to the level of immunoreactive ANG II. ANG II significantly blunts the rise in renin, and renin release in the perfusate is negatively correlated to immunoreactive ANG II levels. Comparison of the ANG I and ANG II levels in in vitro incubated perfusates and circulated perfusates shows that in plasma-injected perfusates the level of immunoreactive ANG II is dependent on both the production of ANG I and its conversion to ANG II by renal and perfusate converting-enzyme activity, and on ANG I and ANG II degradation by the kidney and the perfusate.

Functional evidence for subfornical organ-intrinsic conversion of angiotensin I to angiotensin II

1999 ◽  
Vol 276 (6) ◽  
pp. R1630-R1638 ◽  
Author(s):  
Matthias Rauch ◽  
Herbert A. Schmid
Keyword(s):  
Water Intake ◽  
Renin Angiotensin System ◽  
Subfornical Organ ◽  
Electrophysiological Recording ◽  
High Dose ◽  
Ang Ii ◽  
Angiotensin I ◽  
Angiotensin System ◽  
Subcutaneous Injections

Using extracellular electrophysiological recording in an in vitro slice preparation, we investigated whether ANG I can be locally converted to the functionally active ANG II within the rat subfornical organ (SFO). ANG I and ANG II (10−8–10−7M) excited ∼75% of all neurons tested with both peptides ( n = 25); the remainder were insensitive. The increase in firing rate and the duration and the latency of the responses of identical neurons, superfused with equimolar concentrations of ANG I and ANG II, were not different. The threshold concentrations of the ANG I- and ANG II-induced excitations were both 10−9M. Inhibition of the angiotensin-converting enzyme by captopril (10−4M; n = 8) completely blocked the ANG I-induced excitation, a 10-fold lower dose was only effective in two of four neurons. The AT1-receptor antagonist losartan (10−5M; n = 6) abolished the excitation caused by ANG I and ANG II. Subcutaneous injections of equimolar doses of ANG I and ANG II (200 μl; 2 × 10−4M) in water-sated rats similarly increased water intake by 2.4 ± 0.5 ( n = 16) and 2.7 ± 0.4 ml ( n = 20) after 1 h, respectively. Control rats receiving saline drank 0.07 ± 0.06 ml under these conditions. Pretreatment with a low dose of captopril (2.3 × 10−3M) 10 min before the injection of ANG I caused a water intake of 2.8 ± 0.5 ml ( n = 10), whereas a high dose of captopril (4.6 × 10−1M) suppressed the dipsogenic response of ANG I entirely ( n = 11). These data provide direct functional evidence for an SFO-intrinsic renin-angiotensin system (RAS) and underline the importance of the SFO as a central nervous interface connecting the peripheral with the central RAS.

scholarly journals A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure

2017 ◽  
Vol 312 (5) ◽  
pp. H968-H979 ◽  
Author(s):  
Neeru M. Sharma ◽  
Shyam S. Nandi ◽  
Hong Zheng ◽  
Paras K. Mishra ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Paraventricular Nucleus ◽  
Renin Angiotensin System ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3′-untranslated region (3′-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3′-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF. NEW & NOTEWORTHY Angiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.

scholarly journals Intracrine angiotensin II functions originate from noncanonical pathways in the human heart

2016 ◽  
Vol 311 (2) ◽  
pp. H404-H414 ◽  
Author(s):  
Carlos M. Ferrario ◽  
Sarfaraz Ahmad ◽  
Jasmina Varagic ◽  
Che Ping Cheng ◽  
Leanne Groban ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Functional Significance ◽  
Vascular Remodeling ◽  
Human Heart ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Extended Form ◽  
Angiotensin I ◽  
Angiotensin System ◽  
Ras Genes

Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1–12) [Ang-(1–12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1–12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions.

scholarly journals HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hao Huang ◽  
Yanqin Fan ◽  
Zhao Gao ◽  
Wei Wang ◽  
Ning Shao ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Inflammatory Factors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Inflammatory Injury ◽  
Tnf Α

Abstract Background Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear. Methods Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro. Results The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α. Conclusion Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.

Beta-adrenoceptor-mediated release of angiotensin II from mesenteric arteries

1986 ◽  
Vol 250 (1) ◽  
pp. H144-H148 ◽  
Author(s):  
M. Nakamaru ◽  
E. K. Jackson ◽  
T. Inagami
Keyword(s):  
Renin Angiotensin System ◽  
Ringer Solution ◽  
Mesenteric Arteries ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Beta Adrenoceptor ◽  
Essential Components

Essential components of the renin-angiotensin system such as renin enzymes, angiotensinogen, converting enzyme, and angiotensin receptors have been found in vascular tissues. Locally generated angiotensin (ANG) II may regulate vascular tone by contracting vascular smooth muscle or potentiating sympathetic activity. Recently it was suggested that beta-adrenoceptor-induced enhancement of noradrenergic neurotransmission is mediated by the vascular renin-angiotensin system. The present study was designated to obtain direct evidence for the release of ANG II from the vasculature by beta-adrenoceptor activation. Isolated rat mesenteric arteries were perfused in vitro with Krebs-Ringer solution, and released ANG II was concentrated in a Sep-Pak C-18 cartridge connected to the perfusion system. High-pressure liquid chromatography combined with radioimmunoassay clearly demonstrated the presence of ANG I, II, and a small amount of ANG III in the perfusate. Isoproterenol (10(-9) - 10(-6) M) induced the enhancement of pressor responses to nerve stimulation. This effect was markedly suppressed by propranolol (5 X 10(-7) M), captopril (2 X 10(-6) M), or [Sar1-Ile8]ANG II (10(-6) M). Isoproterenol (10(-9) - 10(-6) M) caused increase in the release of ANG II from mesenteric arteries. The increase in ANG II release during isoproterenol (10(-6) M) infusion was blocked by propranolol (10(-6) M). Captopril (2 X 10(-6) M) also inhibited the increase in ANG II induced by isoproterenol. These results indicate that locally generated ANG II is released from isolated perfused rat mesenteric arteries and its release is mediated by beta-adrenoceptors.

Erythropoietin in COVID-19-Induced Neuroinflammation; EPO Plus Losartan Might be Promising

2020 ◽  
Author(s):  
Reza Nejat ◽  
Ahmad Shahir Sadr ◽  
David Najafi
Keyword(s):  
Inflammatory Mediators ◽  
Renin Angiotensin System ◽  
Oxygen Species ◽  
Ang Ii ◽  
Angiotensin System ◽  
Intracellular Messengers ◽  
The Central Nervous System ◽  
Harmful Effects

Introduction: Neuroinflammation is the inflammatory reaction in the central nervous system (CNS) provoked by diverse insults. This phenomenon results in a cascade of release of inflammatory mediators and intracellular messengers such as reactive oxygen species. The elicited responses are the cause of many neurological and neurodegenerative disorders. Erythropoietin (EPO) has been considered effective in attenuating this inflammatory process in the CNS, yet its administration in COVID-19 needs meticulously designed studies. Discussion: Neuroinflammation in COVID-19 due to probable contribution of renin-angiotensin system dysregulation resulting in surplus of Ang II and owing to the synergistic interaction between this octapeptide and EPO needs special consideration. Both of these compounds increase intracellular Ca2+ which may induce release of cytokine and inflammatory mediators leading to aggravation of neuroinflammation. In addition, Ang II elevates HIF even in normoxia which by itself increases EPO. It is implicated that EPO and HIF may likely increase in patients with COVID-19 which makes administration of EPO to these patients hazardous. Furthermore, papain-like protease of SARS-CoV2 as a deubiquitinase may also increase HIF. Conclusion: It is hypothesized that administration of EPO to patients with COVID-19-induced neuroinflammation may not be safe and in case EPO is needed for any reason in this disease adding of losartan may block AT1R-mediated post-receptor harmful effects of Ang II in synergism with EPO. Inhibition of papain-like protease might additionally decrease HIF in this disease. More in vitro, in vivo and clinical studies are needed to validate these hypotheses.

Snakes and Hypertension

2017 ◽  
Vol 126 (2) ◽  
pp. 321-324
Author(s):  
Edward D. Miller
Keyword(s):  
Blood Pressure ◽  
Renal Artery ◽  
Renovascular Hypertension ◽  
Perfusion Pressure ◽  
Renin Angiotensin System ◽  
Renal Perfusion ◽  
Angiotensin I ◽  
Angiotensin System ◽  
Renal Perfusion Pressure ◽  
Renal Artery Constriction

Abstract Inhibition of Angiotensin Conversion in Experimental Renovascular Hypertension. By Miller ED Jr, Samuels A, Haber E, and Barger AC. Science 1972; 177:1108–9. Reprinted with permission from AAAS. Constriction of the renal artery and controlled reduction of renal perfusion pressure is followed by a prompt increase in systemic renin activity and a concomitant rise in blood pressure in trained, unanesthetized dogs. The elevated blood pressure induced by the renal artery stenosis can be prevented by prior treatment with the nonapeptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, which blocks conversion of angiotensin I to angiotensin II. Further, the nonapeptide can restore systemic pressure to normal in the early phase of renovascular hypertension. These results offer strong evidence that the renin– angiotensin system is responsible for the initiation of hypertension in the unilaterally nephrectomized dog with renal artery constriction.

Role of the renin-angiotensin system in mediating the effects of posture on renal function

1996 ◽  
Vol 271 (1) ◽  
pp. R282-R288 ◽  
Author(s):  
G. A. Reinhart ◽  
T. E. Lohmeier
Keyword(s):  
Renal Function ◽  
Sodium Excretion ◽  
Renal Plasma Flow ◽  
Renin Angiotensin System ◽  
Renal Hemodynamics ◽  
Conscious Dogs ◽  
Plasma Norepinephrine ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

This study was designed to quantitate the influence of the neurohumoral activation associated with orthostatic stress on renal hemodynamics and sodium excretion and, furthermore, to determine the importance of the renin-angiotensin system in mediating these changes in renal function. Seven conscious dogs were studied while lying in the recumbent position and, subsequently, after standing in a supporting sling. Experiments were conducted under control conditions and after plasma angiotensin II (ANG II) concentration was fixed at control levels by chronic infusion of captopril (14 micrograms.kg-1.min-1) and ANG II (0.5 +/- 0.02 ng.kg-1.min-1). During control experiments, 45 min of standing increased plasma renin activity twofold, whereas mean arterial pressure, heart rate, and plasma norepinephrine concentration remained unchanged. During standing, glomerular filtration rate (GFR) and renal plasma flow (RPF) fell to 88 +/- 2 and 77 +/- 3% of recumbent values, respectively, whereas filtration fraction (FF) increased 16 +/- 1%. Additionally, urinary (UNaV) and fractional sodium excretion (FENa) decreased to 27 +/- 6 and 30 +/- 7% of recumbent values, respectively. When plasma ANG II concentration was fixed at control levels during standing, there were no significant changes in GFR, whereas increments in FF and reductions in RPF, UNaV, and FENa were attenuated by 63, 40, 30, and 33%, respectively. These data suggest that, in conscious dogs, standing in a supporting sling causes reflex activation of the sympathetic nervous and renin-angiotensin systems, eliciting reductions in GFR, RPF, and UNaV. Furthermore, ANG II contributes significantly to the effects of passive standing on renal hemodynamics and UNaV.

scholarly journals High intraluminal pressure via H2O2 upregulates arteriolar constrictions to angiotensin II by increasing the functional availability of AT1 receptors

2008 ◽  
Vol 295 (2) ◽  
pp. H835-H841 ◽  
Author(s):  
Zsolt Bagi ◽  
Nora Erdei ◽  
Akos Koller
Keyword(s):  
High Pressure ◽  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Intraluminal Pressure ◽  
Ang Ii ◽  
At1 Receptors ◽  
Angiotensin System ◽  
Dose Dependent

Previously, we found that high intraluminal pressure leads to production of reactive oxygen species (ROS) and also upregulates several components of the renin-angiotensin system in the wall of small arteries. We hypothesized that acute exposure of arterioles to high intraluminal pressure in vitro via increasing ROS production enhances the functional availability of type 1 angiotensin II (Ang II) receptors (AT1 receptors), resulting in sustained constrictions. In arterioles (∼180 μm) isolated from rat skeletal muscle, Ang II elicited dose-dependent constrictions, which decreased significantly by the second application [maximum (max.): from 59% ± 4% to 26% ± 5% at 10−8 M; P < 0.05] in the presence of 80 mmHg of intraluminal pressure. In contrast, if the arterioles were exposed to high intraluminal pressure (160 mmHg for 30 min), Ang II-induced constrictions remained substantial on the second application (max.: 51% ± 3% at 10−8 M). In the presence of Tiron and polyethylene glycol (PEG)-catalase, known to reduce the level of superoxide anion and hydrogen peroxide (H2O2), second applications of Ang II evoked similarly reduced constrictions, even after high-pressure exposure (29% ± 4% at 10−8 M). Furthermore, when arterioles were exposed to H2O2 (for 30 min, 10−7 M, at normal 80 mmHg pressure), Ang II-induced constrictions remained substantial on second applications (59% ± 5% at 10−8 M). These findings suggest that high pressure, likely via inducing H2O2 production, increases the functional availability of AT1 receptors and thus enhances Ang II-induced arteriolar constrictions. We propose that in hypertension–regardless of etiology–high intraluminal pressure, via oxidative stress, enhances the functional availability of AT1 receptors augmenting Ang II-induced constrictions.

Angiotensin-(1–7) potentiates responses to bradykinin but does not change responses to angiotensin I

2006 ◽  
Vol 84 (11) ◽  
pp. 1163-1175 ◽  
Author(s):  
A. Joel Greco ◽  
Ryan G. Master ◽  
Alex Fokin ◽  
Syed R. Baber ◽  
Philip J. Kadowitz
Keyword(s):  
Receptor Antagonist ◽  
Ace Inhibitor ◽  
Renin Angiotensin System ◽  
Product Formation ◽  
Systemic Arterial Pressure ◽  
Ang Ii ◽  
Angiotensin I ◽  
Angiotensin System ◽  
Pressor Responses ◽  
Hoe 140

Angiotensin-(1–7) (Ang-(1–7)), a bioactive peptide in the renin–angiotensin system, has counterregulatory actions to angiotensin II (Ang II). However, the mechanism by which Ang-(1–7) enhances vasodepressor responses to bradykinin (BK) is not well understood. In the present study, the effects of Ang-(1–7) on responses to BK, BK analogs, angiotensin I (Ang I), and Ang II were investigated in the anesthetized rat. The infusion of Ang-(1–7) (55 pmol/min i.v.) enhanced decreases in systemic arterial pressure in response to i.v. injections of BK and the BK analogs [Hyp3, Tyr(Me)8]-bradykinin (HT-BK) and [Phe8ψ (CH2-NH) Arg9]-bradykinin (PA-BK) without altering pressor responses to Ang I or II, or depressor responses to acetylcholine and sodium nitroprusside. The angiotensin-converting enzyme (ACE) inhibitor enalaprilat enhanced responses to BK and the BK analog HT-BK without altering responses to PA-BK and inhibited responses to Ang I. The potentiating effects of Ang-(1–7) and enalaprilat on responses to BK were not attenuated by the Ang-(1–7) receptor antagonist A-779. Ang-(1–7)- and ACE inhibitor-potentiated responses to BK were attenuated by the BK B2 receptor antagonist Hoe 140. The cyclooxygenase inhibitor sodium meclofenamate had no significant effect on responses to BK or Ang-(1–7)-potentiated BK responses. These results suggest that Ang-(1–7) potentiates responses to BK by a selective B2 receptor mechanism that is independent of an effect on Ang-(1–7) receptors, ACE, or cyclooxygenase product formation. These data suggest that ACE inhibitor-potentiated responses to BK are not mediated by an A-779-sensitive mechanism and are consistent with the hypothesis that enalaprilat-induced BK potentiation is due to decreased BK inactivation.

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