Different mechanisms of acute versus long‐term antihypertensive effects of soluble epoxide hydrolase inhibition: Studies in Cyp1a1‐Ren‐2 transgenic rats

Recent studies have shown that the long‐term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin‐II (AngII)‐dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII‐dependent hypertension. AngII‐dependent malignant hypertension was induced by 10 days’ dietary administration of indole‐3‐carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1‐Ren‐2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP‐lowering effects of sEH inhibition in I3C‐induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid in I3C‐induced rats elicited dose‐dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP‐lowering effect of sEH inhibition in I3C‐induced Cyp1a1‐Ren‐2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin–angiotensin system activity. Long‐term antihypertensive action of cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid in I3C‐induced Cyp1a1‐Ren‐2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.     

Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren‐2 transgenic hypertensive rats with aorto‐caval fistula

The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren‐2 transgenic rats (TGR), a model of angiotensin II (ANG II)‐dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto‐caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin‐angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy]benzoic acid (c‐AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin‐converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.     

Genetic clamping of renin gene expression induces hypertension and elevation of intrarenal Ang II levels of graded severity in Cyp1a1-Ren2 transgenic rats.

INTRODUCTION: Transgenic rats with inducible angiotensin II (Ang II)-dependent hypertension (strain name: TGR[Cyp1a1-Ren2]) were generated by inserting the mouse Ren2 renin gene, fused to the cytochrome P450 1a1 (Cyp1a1) promoter, into the genome of the rat. The present study was performed to characterise the changes in plasma and kidney tissue Ang II levels and in renal haemodynamic function in Cyp1a1-Ren2 rats following induction of either slowly developing or malignant hypertension in these transgenic rats. MATERIALS AND METHODS: Arterial blood pressure (BP) and renal haemodynamics and excretory function were measured in pentobarbital sodium-anaesthetised Cyp1a1- Ren2 rats fed a normal diet containing either a low dose (0.15%, w/w for 1415 days) or high dose (0.3%, w/w for 1112 days) of the aryl hydrocarbon indole-3-carbinol (I3C) to induce slowly developing and malignant hypertension, respectively. In parallel experiments, arterial blood samples and kidneys were harvested for measurement of Ang II levels by radioimmunoassay. RESULTS: Dietary I3C increased plasma renin activity (PRA), plasma Ang II levels, and arterial BP in a dose-dependent manner. Induction of different fixed levels of renin gene expression and PRA produced hypertensive phenotypes of varying severity with rats developing either mild or malignant forms of hypertensive disease. Administration of I3C, at a dose of 0.15% (w/w), induced a slowly developing form of hypertension whereas administration of a higher dose (0.3%) induced a more rapidly developing hypertension and the clinical manifestations of malignant hypertension including severe weight loss. Both hypertensive phenotypes were characterised by reduced renal plasma flow, increased filtration fraction, elevated PRA, and increased plasma and intrarenal Ang II levels. These I3C-induced changes in renal haemodynamics, PRA and kidney Ang II levels were more pronounced in Cyp1a1-Ren2 rats with malignant hypertension. Chronic administration of the AT1-receptor antagonist, hypertension, the associated changes in renal haemodynamics, and the augmentation of intrarenal Ang II levels. CONCLUSIONS: Activation of AT1-receptors by Ang II generated as a consequence of induction of the Cyp1a1-Ren2 transgene mediates the increased arterial pressure and the associated reduction of renal haemodynamics and enhancement of intrarenal Ang II levels in hypertensive Cyp1a1-Ren2 transgenic rats.     

Angiotensin converting enzyme 2 in the kidney

1. Angiotensin converting enzyme 2 (ACE2) is an important homeostatic component of the renin angiotensin system (RAS). ACE2 both degrades the vasoconstrictor, angiotensin II and generates the potent vasodilator peptide, angiotensin 1-7. These actions counterbalance those of ACE. 2. ACE2 is highly expressed in the healthy kidney, particularly in the proximal tubules, where it colocalizes with ACE and angiotensin receptors. 3. Kidney disease and subtotal nephrectomy is associated with a reduction in renal ACE2 expression, possibly facilitating the damaging effects of angiotensin II in the failing kidney. Acquired or genetic ACE2 deficiency also appears to exacerbate renal damage and albuminuria in experimental models, supporting this hypothesis. 4. ACE2 also has an important role in blood pressure control. Many models of hypertension are associated with reduced ACE2 expression. Although ACE2 KO animals are normotensive, in states associated with activation of the RAS, ACE2 overexpression improves blood pressure control and reduces angiotensin responsiveness.     

Antihypertensive action of soluble epoxide hydrolase inhibition in Ren‐2 transgenic rats is mediated by suppression of the intrarenal renin–angiotensin system

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Protective arms of the renin–angiotensin‐system in neurological disease

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The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases

The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin-converting enzyme (ACE) comprises the classical RAS. The non-classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1-7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non-classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.     

Fragments of Nle3‐angiotensin(1–7) accelerate healing in dermal models

Abstract: The renin angiotensin system (RAS) has been shown to be present in dermal tissue and exogenous peptides from the RAS accelerates healing and reduces scarring. An analogue of Angiotensin(1–7) [A(1–7)], Norleucine³‐A(1–7) [Nle³‐A(1–7)], is the lead compound under development for treatment of dermal injuries. As proteases are prevalent in wounded tissue and at very high levels in chronic wounds, the ability of fragments of Nle³‐A(1–7) to accelerate healing and the effect of proteases on the peptide were determined. Daily application of fragments of Nle³‐A(1–7) of five or six amino acids accelerated healing in two models of dermal injury. In addition, the peptide was found to be stable (not substantially degraded) after incubation for 4 h in the presence of Cathepsin G, collagenases blend (from clostridium), matrix metalloprotease [MMP] 2, MMP 3, MMP 9, elastase (human leukocytic or porcine pancreatic) or plasmin. Only kallikrein, an enzyme known to cleave peptides of the RAS, cleaved the peptide into two major fragments one of which was identified as NorLeu³‐A(1–4). These data support the activity of Nle³‐A(1–7) on dermal wounds.     

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy.     

Cardiovascular and Renal Review: Pharmacology of Angiotensin II Receptor Antagonists: Comparison with Renin Inhibitors and Angiotensin-Converting Enzyme Inhibitors

Nonpeptide angiotensin II (ANG II) receptor antagonists are a new class of inhibitors of the renin angiotensin system (RAS). Several ANG II receptor antagonists are currently in clinical development for the treatment of hypertension and heart failure. The discovery of these compounds follows many years of research on renin and the spectacular success of angiotensin converting enzyme (ACE) inhibitors, both as therapeutic agents and pharmacological tools. By inhibiting the interaction of ANG II with its receptor(s), studies utilising ANG II receptor antagonists have furthered our understanding of the RAS. This class of compounds may provide an interesting alternative to ACE inhibitors for the clinical management of hypertension and heart failure. The present article examines the comparative preclinical pharmacology of ANG II receptor antagonists, ACE inhibitors and renin inhibitors, with two objectives: 1) to demonstrate how our knowledge of the RAS has been extended utilising these three classes of pharmacological tools; and, 2) to review how ANG II receptor antagonists have been used in preclinical animal models with respect to their potential clinical indications.     

Antifibrotic peptide N‐acetyl‐Ser‐Asp‐Lys‐Pro (Ac‐SDKP): Opportunities for angiotensin‐converting enzyme inhibitor design

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OBG‐like ATPase 1 inhibition attenuates angiotensin II‐induced hypertrophic response in human ventricular myocytes via GSK‐3beta/beta‐catenin signalling

Obg‐like ATPase 1 (OLA1) that possesses both GTP and ATP hydrolyzing activities has been shown to be involved in translational regulation of cancer cell growth and survival. Also, GSK3β signalling has been implicated in cardiac development and disease. However, the role of OLA1 in pathological cardiac hypertrophy is unknown. We sought to understand the mechanism by which OLA1 regulates GSK3β‐β‐Catenin signalling and its functional significance in angiotensin‐II (ANG II)‐induced cardiac hypertrophic response. OLA1 function and its endogenous interaction with GSK3β/β‐catenin signalling in cultured human ventricular cardiomyocytes (AC16 cells) and mouse hearts (in vivo) was evaluated with/without ANG II‐stimulated hypertrophic response. ANG II administration in mice increases myocardial OLA1 protein expression with a corresponding increase in GSK3β phosphorylation and decrease in β‐Catenin phosphorylation. Cultured cardiomyocytes treated with ANG II show endogenous interaction between OLA1 and GSK3β, nuclear accumulation of β‐Catenin and significant increase in cell size and expression of hypertrophic marker genes such as atrial natriuretic factor (ANF; NPPA) and β‐myosin heavy chain (MYH7). Intriguingly, OLA1 inhibition attenuates the above hypertrophic response in cardiomyocytes. Taken together, our data suggest that OLA1 plays a detrimental role in hypertrophic response via GSK3β/β‐catenin signalling. Translation strategies to target OLA1 might potentially limit the underlying molecular derangements leading to left ventricular dysfunction in patients with maladaptive cardiac hypertrophy.     

Endothelin receptor blockade does not affect blood pressure or angiotensin II levels in CYP1A1-Ren-2 transgenic rats with acutely induced hypertension

We found previously that selective blockade of endothelin ETA receptors is superior to nonselective ET_A/ET_B in attenuating hypertension and survival rate in Ren-2 transgenic rats (TGR). In the present pilot study, we were interested in whether similar effects will be found in TGR with inducible malignant hypertension (iTGR; official strain name Cyp1A1-Ren-2rats), which were derived from the original Ren-2 transgenic rat strain. Studies were performed in three-month old male iTGR. Treatment with either bosentan, a non-selective ET_A/ET_B, or with atrasentan, a selective ET_A receptor blocker, was started on day 2 of the experiment. Feeding with indole-3-carbinole (I3C; 0.3% in rat chow), a natural xenobiotic which activates the Cyp1a1 promoter of the mouse Ren-2 gene, began on day 3 and lasted for 4 days until day 6. Systolic BP, body weight, plasma ANG II and tissue ANG II and ET-1 concentrations were determined daily. Severe hypertension developed as early as 1 day after beginning of I3C feeding which was accompanied by a significant reduction in body weight and by increases in plasma and tissue ANG II and left ventricle ET-1 concentrations. Atrasentan or bosentan had no effects on the rise in BP or plasma and tissue ANG II concentrations but prevented the rise in heart ventricle ET-1 concentration. Our data show that blockade of the ET system does not prevent or attenuate the rapid development of severe hypertension in iTGR; a long-term protective effect of ET blockade on cardiac (and renal) damage, however, cannot be excluded and awaits further investigations.     

Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

Aims

To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension.

Methods and results

Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91^phox (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91^phox, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats.

Conclusion

These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension.     

Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats

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Angiotensin AT1 receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

1. Renal tubular epithelial cells can undergo epithelial to mesenchymal transition (EMT) under hyperglycaemic conditions, which is associated with renal interstitial fibrosis. Activation of the renin–angiotensin system (RAS) is involved in diabetic nephropathy. The present study investigated the positive role of angiotensin AT₁ receptors in high glucose‐induced EMT in cultured tubular epithelial cells. 2. A rat kidney proximal tubular epithelial cell line (NRK‐52E) was used in the present study. Levels of EMT makers, namely E‐cadherin and vimentin, were estimated using fluorescence immunocytochemistry, mRNA levels of angiotensinogen (AGT), angiotensin‐converting enzyme (ACE) and AT₁ receptors were determined by real‐time polymerase chain reaction, protein levels of E‐cadherin, vimentin, fibronectin, matrix metallopeptidase (MMP)‐9 and phosphorylated extracellular signal‐regulated kinase (ERK) 1/2 were analysed by western blotting and the concentrations of angiotensin (Ang) II and transforming growth factor (TGF)‐β1 in the culture medium were determined by enzyme immunoassay and ELISA. 3. High glucose (30 mmol/L) induced EMT and increased the synthesis of fibronectin and MMP‐9. Furthermore, high glucose increased AGT, ACE and AT₁ receptor mRNA levels, as well as AngII and TGF‐β1 concentrations in the culture medium and ERK1/2 phosphorylation. Pretreatment of cells for 15 min with the AT₁ receptor antagonist losartan (10^?5 mol/L) attenuated high glucose‐induced increases in TGF‐β1 and ERK1/2 phosphorylation and reduced EMT, as well as the consequent synthesis of fibronectin and MMP‐9. 4. The results of the present study suggest that the activated local RAS mediates high glucose‐induced EMT. By activating AT₁ receptors and stimulating TGF‐β1 synthesis, the elevated local RAS participates in high glucose‐induced EMT and increased extracellular matrix secretion.     

Renin and the (pro)renin receptor in the renal collecting duct: Role in the pathogenesis of hypertension

The intrarenal renin–angiotensin system (RAS) plays a critical role in the pathogenesis and progression of hypertension and kidney disease. In angiotensin (Ang) II‐dependent hypertension, collecting duct renin synthesis and secretion are stimulated despite suppression of juxtaglomerular (JG) renin. This effect is mediated by the AngII type I receptor (AT₁R), independent of blood pressure. Although the regulation of JG renin has been extensively studied, the mechanisms by which renin is regulated in the collecting duct remain unclear. The augmentation of renin synthesis and activity in the collecting duct may provide a pathway for additional generation of intrarenal and intratubular AngII formation due to the presence of angiotensinogen substrate and angiotensin‐converting enzyme in the nephron. The recently described (pro)renin receptor ((P)RR) binds renin or prorenin, enhancing renin activity and fully activating the biologically inactive prorenin peptide. Stimulation of (P)RR also activates intracellular pathways related to fibrosis. Renin and the (P)RR are augmented in renal tissues of AngII‐dependent hypertensive rats. However, the functional contribution of the (P)RR to enhanced renin activity in the collecting duct and its contribution to the development of hypertension and kidney disease have not been well elucidated. This review focuses on recent evidence demonstrating the mechanism of renin regulation in the collecting ducts and its interaction with the (P)RR. The data suggest that renin–(P)RR interactions may induce stimulation of intracellular pathways associated with the development of hypertension and kidney disease.     

Novel concept in the mechanism of injury and protection of gastric mucosa: role of renin-angiotensin system and active metabolites of angiotensin

The term cytoprotection pioneered by Robert and colleagues has been introduced to describe the remarkable ability of endogenous and exogenous prostaglandins (PGs) to prevent acute gastric hemorrhagic lesions induced by noxious stimuli such as ethanol, bile acids, hiperosmolar solutions and nonsteroidal anti-inflammatory agents such as aspirin. Since that time many factors were implicated to possess gastroprotective properties such as growth factors including epidermal growth factor (EGF) and transforming factor alpha (TGFα), vasodilatory mediators such as nitric oxide (NO) and calcitonin gene related peptide (CGRP) as well as appetite gut hormones including gastrin and cholecystokinin (CCK), leptin and recently ghrelin. This protective action of gut peptides has been attributed to the release of PG but question remains whether another peptide angiotensin, the classic component of the systemic and local renin-angiotensin system (RAS) could be involved in the mechanism of gastric integrity and gastroprotection. After renin stimulation, the circulating angiotensin I is converted to angiotensin II (ANG II) by the activity of the Angiotensin Converting Enzyme (ACE). The ANG II acting via its binding to two major receptor subtypes the ANG type 1 (AT1) and type 2 (AT2) has been shown be activated during stress and to contribute to the pathogenesis of cold stress- and ischemia-reperfusion-induced gastric lesions. All bioactive angiotensin peptides can be generated not only in systemic circulation, but also locally in several tissues and organs. Recently the new functional components of RAS, such as Ang-(1-7), Ang IV, Ang-(1-12) and novel pathways ACE2 have been described suggesting the gastroprotective role for the novel ANG II metabolite, Ang-(1-7). The fact that Ang-(1-7) is produced in excessive amounts in the gastric mucosa of rodents and that pretreatment by Ang-(1-7) exhibits a potent gastroprotective activity against the gastric lesions induced by cold-restraint stress suggests that this and possibly other vasoactive metabolites of ANG II pathway could be involved in the mechanism of gastric integrity and gastroprotection. This review summarizes the novel gastroprotective factors and mechanisms associated with metabolic fate of systemic and local RAS activation with major focus to recent advancement in the angiotensin pathways in the gut integrity.