scholarly journals Angiotensin-(1-7) and Its Effects in the Kidney

2009 ◽  
Vol 9 ◽  
pp. 522-535 ◽  
Author(s):  
Marc Dilauro ◽  
Kevin D. Burns
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Mesangial Cells ◽  
Gene Knockout ◽  
Collecting Duct ◽  
Tyrosine Phosphatase ◽  
The Body ◽  
Ang Ii

Angiotensin-(1-7) (Ang-[1-7]) is a heptapeptide member of the renin-angiotensin system (RAS), and acts as a vasodilator and antagonist of angiotensin II (Ang II) in the vasculature. The role of Ang-(1-7) in regulating kidney function is not well understood. Within the kidneys, Ang-(1-7) is generated by angiotensin-converting enzyme 2 (ACE2)–mediated degradation of Ang II, sequential cleavage of the precursor angiotensin I (Ang I) by ACE2 and ACE, or the actions of brush-border membrane peptidases on Ang I. Ang-(1-7) mediates its effects via binding to kidney Mas receptors, although some actions may occur via Ang II AT1or AT2receptors.In vitrostudies suggest that Ang-(1-7) is an intrarenal vasodilator. Ang-(1-7) has been reported to induce either natriuresis/diuresis or sodium and water retention, via modulation of sodium transporters in the proximal tubule and loop of Henle, and collecting duct water transport. In the proximal tubule, Ang-(1-7) antagonizes growth-promoting signaling pathways via activation of a protein tyrosine phosphatase, whereas in mesangial cells, Ang-(1-7) stimulates cell growth via activation of mitogen-activated protein kinases. The phenotype of the Mas gene knockout mouse suggests that Ang-(1-7)–signaling events exert cardiovascular protection by regulating blood pressure, and by limiting production of reactive oxygen species and extracellular matrix proteins. Ang-(1-7) also protects against renal injury in the renal wrap hypertension model, independent of effects on blood pressure. In diabetic nephropathy, however, the role of Ang-(1-7) on disease progression remains unclear. In summary, Ang-(1-7) and its receptor Mas have emerged as important components of the intrarenal RAS. The signaling and downstream effects of Ang-(1-7) in the kidney are complex and appear to be cell specific. The body of evidence suggests that Ang-(1-7) is protective against endothelial dysfunction or Ang II–stimulated proximal tubular injury, although the overall effects on glomerular function require further study.

scholarly journals Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension

2019 ◽  
Vol 51 (4) ◽  
pp. 97-108 ◽  
Author(s):  
Xiao C. Li ◽  
Xiaowen Zheng ◽  
Xu Chen ◽  
Chunling Zhao ◽  
Dongmin Zhu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Pressure Regulation ◽  
Blood Pressure Homeostasis ◽  
Induced Hypertension ◽  
Basal Blood Pressure

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+/K+-ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+/K+-ATPase in proximal tubular Na+ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

scholarly journals Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling

2015 ◽  
Vol 309 (8) ◽  
pp. C541-C550 ◽  
Author(s):  
Carla P. Carneiro de Morais ◽  
Juliano Z. Polidoro ◽  
Donna L. Ralph ◽  
Thaissa D. Pessoa ◽  
Maria Oliveira-Souza ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
G Protein ◽  
Extracellular Fluid ◽  
The Body ◽  
Type I ◽  
Ang Ii ◽  
Receptor Signaling

Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na+/H+ exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na+-dependent intracellular pH recovery. We found that 10−7 M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization.

scholarly journals Angiotensin II Type 2 Receptor

Hypertension ◽  
2021 ◽  
Author(s):  
Naureen Fatima ◽  
Sanket N. Patel ◽  
Tahir Hussain
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Kidney Diseases ◽  
Gene Knockout ◽  
The Body ◽  
Sodium Reabsorption ◽  
Ang Ii ◽  
Organ Protection ◽  
Organ Systems

The renin-angiotensin system is of vital significance not only in the maintenance of blood pressure but also because of its role in the pathophysiology of different organ systems in the body. Of the 2 Ang II (angiotensin II) receptors, the AT 1 R (Ang II type 1 receptor) has been extensively studied for its role in mediating the classical functions of Ang II, including vasoconstriction, stimulation of renal tubular sodium reabsorption, hormonal secretion, cell proliferation, inflammation, and oxidative stress. The other receptor, AT 2 R (Ang II type 2 receptor), is abundantly expressed in both immune and nonimmune cells in fetal tissue. However, its expression is increased under pathological conditions in adult tissues. The role of AT 2 R in counteracting AT 1 R function has been discussed in the past 2 decades. However, with the discovery of the nonpeptide agonist C21, the significance of AT 2 R in various pathologies such as obesity, hypertension, and kidney diseases have been examined. This review focuses on the most recent findings on the beneficial effects of AT 2 R by summarizing both gene knockout studies as well as pharmacological studies, specifically highlighting its importance in blood pressure regulation, obesity/metabolism, organ protection, and relevance in the treatment of coronavirus disease 2019 (COVID-19).

Abstract 011: An Orally Absorbable Potent NHE3 Inhibitor Attenuates Angiotensin II-induced Hypertension Primarily by Inhibiting NHE3 in the Proximal Tubule of the Kidney

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Hoang Nguyen ◽  
Jia L Zhuo
Keyword(s):  
Proximal Tubule ◽  
The Body ◽  
High Salt ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Small Intestines ◽  
Orally Active ◽  
Nhe3 Inhibitor

We have recently shown that angiotensin (ANG II)-induced hypertension was attenuated in mice with global ( Nhe3 -/- ) and Nhe3 -/- mice with transgenic rescue of the NHE3 gene selectively in small intestines (tg Nhe3 -/- ), suggesting an important role of NHE3 in the development of ANG II-dependent hypertension. In this study, we specifically tested whether the pharmacological inhibition of NHE3 mainly in the proximal tubules of the kidney attenuates ANG II-dependent hypertension induced by a low and slow pressor dose of ANG II supplemented with a high salt diet. Overall, 9 groups (n=5-12) of adult male C57BL/6J mice were infused with or without ANG II (500 μg/kg/day, i.p. via minipump) and supplemented with or without a 2% NaCl diet to slowly and moderately increase systolic blood pressure (SBP) in 2 weeks. ANG II alone increased SBP from 116 ± 2 mmHg to 140 ± 2 mmHg ( p <0.01), and supplement of ANG II with a 2% NaCl diet further increased SBP to 147 ± 4 mmHg ( p <0.05). Concurrent treatment with an orally active, absorbable NHE3 inhibitor AVE0657 (Sanofi-Aventis; 20 mg/kg/day, p.o.) significantly decreased SBP to 125 ± 4 mmHg in ANG II-infused mice ( p <0.01), and to 134 ± 6 mmHg in ANG II-infused mice supplemented with 2% NaCl ( p <0.01), respectively. Further treatment with AVE0657 and losartan, an AT 1 receptor blocker (20 mg/kg/day, p.o.), completely normalize SBP in mice treated with ANG II and 2% NaCl to control (115 ± 5 mmHg, p <0.01). In the kidney, AVE0657 significantly increased 24h urinary Na + excretion from 157.1 ± 6.7 to 207.7 ± 8.1 μmol/24h ( p <0.01) without altering 24h urine excretion or SBP. Furthermore, AVE0657 did not significantly alter 24 h fecal Na + excretion in non ANG II-infused (4.99 ± 0.37 μmol/24h, n.s.) or ANG II-infused mice (4.19 ± 0.67 μmol/24h, n.s.), compared with control (4.02 ± 0.20 μmol/24h, n.s. ) or global Nhe3 -/- mice (50.8 ± 0.8 μmol/24h, p <0.01). Since small intestines in the gut and the proximal tubules of the kidney express the vast majority of NHE3 in the body, these results provide preclinical evidence and perspectives that orally absorbable NHE3 inhibitors may be pharmacologically beneficial to prevent and treat hypertension induced by ANG II and a high salt, mainly by inhibiting NHE3 in the proximal tubule of the kidney.

scholarly journals Mechanisms of proximal tubule sodium transport regulation that link extracellular fluid volume and blood pressure

2010 ◽  
Vol 298 (4) ◽  
pp. R851-R861 ◽  
Author(s):  
Alicia A. McDonough
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Flow Rate ◽  
Sodium Transport ◽  
Extracellular Fluid ◽  
Fluid Volume ◽  
The Body ◽  
Extracellular Fluid Volume ◽  
Ang Ii ◽  
Salt Diet

One-hundred years ago, Starling articulated the interdependence of renal control of circulating blood volume and effective cardiac performance. During the past 25 years, the molecular mechanisms responsible for the interdependence of blood pressure (BP), extracellular fluid volume (ECFV), the renin-angiotensin system (RAS), and sympathetic nervous system (SNS) have begun to be revealed. These variables all converge on regulation of renal proximal tubule (PT) sodium transport. The PT reabsorbs two-thirds of the filtered Na+ and volume at baseline. This fraction is decreased when BP or perfusion pressure is increased, during a high-salt diet (elevated ECFV), and during inhibition of the production of ANG II; conversely, this fraction is increased by ANG II, SNS activation, and a low-salt diet. These variables all regulate the distribution of the Na+/H+ exchanger isoform 3 (NHE3) and the Na+-phosphate cotransporter (NaPi2), along the apical microvilli of the PT. Natriuretic stimuli provoke the dynamic redistribution of these transporters along with associated regulators, molecular motors, and cytoskeleton-associated proteins to the base of the microvilli. The lipid raft-associated NHE3 remains at the base, and the nonraft-associated NaPi2 is endocytosed, culminating in decreased Na+ transport and increased PT flow rate. Antinatriuretic stimuli return the same transporters and regulators to the body of the microvilli associated with an increase in transport activity and decrease in PT flow rate. In summary, ECFV and BP homeostasis are, at least in part, maintained by continuous and acute redistribution of transporter complexes up and down the PT microvilli, which affect regulation of PT sodium reabsorption in response to fluctuations in ECFV, BP, SNS, and RAS.

scholarly journals Endothelial-derived extracellular microRNA-92a promotes arterial stiffness by regulating phenotype changes of vascular smooth muscle cells

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Chen Wang ◽  
Haoyu Wu ◽  
Yuanming Xing ◽  
Yulan Ye ◽  
Fangzhou He ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Arterial Stiffness ◽  
Vascular Smooth Muscle ◽  
Vascular Endothelial Cells ◽  
Locked Nucleic Acid ◽  
Vascular Endothelial ◽  
Ang Ii

AbstractEndothelial dysfunction and vascular smooth muscle cell (VSMC) plasticity are critically involved in the pathogenesis of hypertension and arterial stiffness. MicroRNAs can mediate the cellular communication between vascular endothelial cells (ECs) and neighboring cells. Here, we investigated the role of endothelial-derived extracellular microRNA-92a (miR-92a) in promoting arterial stiffness by regulating EC–VSMC communication. Serum miR-92a level was higher in hypertensive patients than controls. Circulating miR-92a level was positively correlated with pulse wave velocity (PWV), systolic blood pressure (SBP), diastolic blood pressure (DBP), and serum endothelin-1 (ET-1) level, but inversely with serum nitric oxide (NO) level. In vitro, angiotensin II (Ang II)-increased miR-92a level in ECs mediated a contractile-to-synthetic phenotype change of co-cultured VSMCs. In Ang II-infused mice, locked nucleic acid-modified antisense miR-92a (LNA-miR-92a) ameliorated PWV, SBP, DBP, and impaired vasodilation induced by Ang II. LNA-miR-92a administration also reversed the increased levels of proliferative genes and decreased levels of contractile genes induced by Ang II in mouse aortas. Circulating serum miR-92a level and PWV were correlated in these mice. These findings indicate that EC miR-92a may be transported to VSMCs via extracellular vesicles to regulate phenotype changes of VSMCs, leading to arterial stiffness.

Abstract 014: Collecting Duct Specific Deletion of the (Pro)renin Receptor Modulates ENaC Expression

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Kai Song ◽  
Nikita Abraham ◽  
Shuping Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Cre Recombinase ◽  
Protein Isoforms ◽  
Ang Ii ◽  
Renal Tubular ◽  
Renal Expression ◽  
Specific Deletion

The renal tubular (pro)renin receptor (PRR) has been shown to modulate water balance, blood pressure and Na + homeostasis. We recently reported that inducible nephron wide deletion of the PRR results in Na + wasting, reduced epithelial Na + channel (ENaC) expression in the kidney and attenuated hypertensive response to angiotensin-II (Ang-II) infusion. In this study, we examined the effects of PRR deletion in collecting duct (CD) specific mouse models targeting either the principal cells (PC) or intercalated cells (IC). PC-specific PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring AQP-2 Cre recombinase. Compared to floxed mice, PC specific KO PRR mice had no differences in PRR immunostaining but had 50% reduction in PRR mRNA in micro-dissected cortical CDs. No differences in blood pressure were observed between the two groups at baseline or following Ang-II infusion at 600 ng/kg/min. Similarly, plasma renin concentration and renal expression of ENaC protein isoforms were comparable between the two groups. To achieve IC-specific PRR deletion, floxed PRR mice were bred with mice expressing B-1 Cre recombinase. Compared to floxed controls, IC-specific PRR KO mice were smaller (KO body weight: 5.9 ± 1.3 g vs controls: 11.1± 1.2 g) and did not survive beyond 30 days after birth. IC-specific PRR KO mice also demonstrated marked reduction in renal medullary PRR immunostaining along with decreased renal expression of ENaC-α protein (50% reduction compared to controls), similar to the findings in nephron wide deletion of PRR. Taken together, these findings suggest that IC specific deletion of PRR but not PC-specific deletion modulates renal ENaC expression. Further studies evaluating ENaC activity in isolated cortical CDs from PC and IC specific PRR KO mice will help delineate the functional role of CD PRR in Na + homeostasis.

Role of PKC and calcium in modulation of effects of angiotensin II on sodium transport in proximal tubule

2003 ◽  
Vol 284 (4) ◽  
pp. F688-F692 ◽  
Author(s):  
Zhaopeng Du ◽  
William Ferguson ◽  
Tong Wang
Keyword(s):  
Proximal Tubule ◽  
Intracellular Calcium ◽  
Critical Role ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Fluid Absorption ◽  
Physiological Concentration ◽  
High Concentrations

It has been well documented that low concentrations of ANG II (10−11 to 10−10 M) stimulate, whereas high concentrations of ANG II (10−8 to 10−5 M) inhibit Na+transport in proximal tubules of rat and rabbit kidneys. Measured ANG II concentration in proximal tubular fluid is in the nanomolar range. In the present study, we investigated the role of PKC, intracellular Ca2+, and cAMP in modulating the effects of luminal ANG II on Na+ absorption by microperfusion techniques in rabbit superficial segment of proximal tubules in vitro. We confirmed that ANG II (10−9 M) had no change on fluid absorption ( J v); however, fluid absorption increased significantly when 10−9 M ANG II and 3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester (TMB-8), a blocker of intracellular calcium mobilization, were added together. In contrast, ANG II significantly decreased J v when PKC was inhibited. When 10−9 M ANG II was present together with 1-(5-isoquinolinesulfonyl)-2-mehtylpiperazine and TMB-8, no significant change of J v occurred. Inhibition of endogenous cAMP activity by a PKA inhibitor did not change either basal or ANG II-stimulated fluid absorption. Our results indicate that ANG II regulates Na+ absorption by a cAMP-independent mechanism and that PKC and intracellular calcium both play a critical role in modulating the effects of physiological concentration of ANG II on proximal tubule transport. Balance between these two cytosolic messengers modulates the effects of ANG II on fluid absorption in the proximal tubule.

Angiotensin I-converting enzyme activity in tubular fluid along the rat nephron

1997 ◽  
Vol 272 (3) ◽  
pp. F405-F409 ◽  
Author(s):  
D. E. Casarini ◽  
M. A. Boim ◽  
R. C. Stella ◽  
M. H. Krieger-Azzolini ◽  
J. E. Krieger ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Proximal Tubule ◽  
Mesangial Cells ◽  
Collecting Duct ◽  
Physiological Role ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Angiotensin I Converting Enzyme ◽  
Ace Activity

The activity of angiotensin I-converting enzyme (ACE) was determined in tubular fluid collected from several portions of the rat nephron and urine and in total and efferent arteriolar blood using hippuryl-L-His-Leu as substrate. ACE activity decreased 30% from the pre- to the postglomerular arterioles (P < 0.001), suggesting a role of the glomerulus in ACE clearance. The enzyme activity was found to be present throughout the rat nephron. However, the highest activities were found in the proximal tubule and urine (0.692 +/- 0.007 and 1.05 +/- 0.015 pmol x microl(-1) x min(-1), respectively). Compared with other segments, ACE activity decreased from the initial portion of the proximal tubule to the distal nephron and increased again in the urine. Along the proximal tubule, ACE was secreted and degraded and/or reabsorbed and then secreted again into the collecting duct; no ACE activity was found in the late distal tubule, but a high level was detected in the urine, indicating a potential physiological role in the inactivation of the kinins formed by kallikrein beyond the connecting tubules. Moreover, the possible role of mesangial cells (MC) in the decrease of intraglomerular ACE was also evaluated. The analysis of ACE gene showed that MC in culture are able to express ACE mRNA. Moreover, ACE is produced as an ectoenzyme and as a secreted form of the enzyme, indicating a potential effect of local angiotensin II production on MC function.

scholarly journals Review: Evidence for a functional intracellular angiotensin system in the proximal tubule of the kidney

2012 ◽  
Vol 302 (5) ◽  
pp. R494-R509 ◽  
Author(s):  
Brianne Ellis ◽  
Xiao C. Li ◽  
Elisa Miguel-Qin ◽  
Victor Gu ◽  
Jia L. Zhuo
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Renin Angiotensin System ◽  
Proximal Tubules ◽  
Renal Physiology ◽  
The Novel ◽  
Ang Ii ◽  
Angiotensin System ◽  
Proximal Tubular

ANG II is the most potent and important member of the classical renin-angiotensin system (RAS). ANG II, once considered to be an endocrine hormone, is now increasingly recognized to also play novel and important paracrine (cell-to-cell) and intracrine (intracellular) roles in cardiovascular and renal physiology and blood pressure regulation. Although an intracrine role of ANG II remains an issue of continuous debates and requires further confirmation, a great deal of research has recently been devoted to uncover the novel actions and elucidate underlying signaling mechanisms of the so-called intracellular ANG II in cardiovascular, neural, and renal systems. The purpose of this article is to provide a comprehensive review of the intracellular actions of ANG II, either administered directly into the cells or expressed as an intracellularly functional fusion protein, and its effects throughout a variety of target tissues susceptible to the impacts of an overactive ANG II, with a particular focus on the proximal tubules of the kidney. While continuously reaffirming the roles of extracellular or circulating ANG II in the proximal tubules, our review will focus on recent evidence obtained for the novel biological roles of intracellular ANG II in cultured proximal tubule cells in vitro and the potential physiological roles of intracellular ANG II in the regulation of proximal tubular reabsorption and blood pressure in rats and mice. It is our hope that the new knowledge on the roles of intracellular ANG II in proximal tubules will serve as a catalyst to stimulate further studies and debates in the field and to help us better understand how extracellular and intracellular ANG II acts independently or interacts with each other, to regulate proximal tubular transport and blood pressure in both physiological and diseased states.

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