Effects of angiotensin II and nonpeptide receptor antagonists on transduction pathways in rat proximal tubule

1992 ◽  
Vol 263 (4) ◽  
pp. C750-C758 ◽  
Author(s):  
J. Poggioli ◽  
G. Lazar ◽  
P. Houillier ◽  
J. P. Gardin ◽  
J. M. Achard ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Inositol Phosphates ◽  
Inositol Trisphosphate ◽  
Receptor Activation ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
At1 Antagonist ◽  
Rat Proximal Tubule

Because the presence of the angiotensin II (ANG II)-dependent phosphoinositide hydrolysis has been questioned from studies in proximal cells in culture, we looked for this transduction pathway in suspension of freshly isolated rat proximal tubule fragments. ANG II-receptor activation induced a prompt (within 15 s) and sustained increase in [3H]inositol phosphates (IPs; inositol trisphosphate, inositol bisphosphate, and inositol monophosphate). In fura-2-loaded tubules, it elicited a rapid and biphasic rise in cytosolic free calcium ([Ca2+]i) with an early peak (within 15 s) followed by a plateau. The peak was maintained in the absence of extracellular calcium. ANG II-induced inositol trisphosphate and [Ca2+]i rises showed a similar dose dependency, with a 50% effective concentration (EC50) of 2.9 and 5.5 nM, respectively. We checked that ANG II inhibited basal (EC50 4.4 nM) and parathyroid hormone- and forskolin-stimulated cAMP production, the latter effect being inhibited by pertussis toxin pretreatment. The effects of ANG II on IPs and [Ca2+]i were inhibited by the ANG II receptor subtype 1 (AT1) antagonist losartan and not by the ANG II receptor subtype 2 (AT2) antagonists PD 123177 and PD 123319. The effect of ANG II on forskolin-stimulated cAMP was inhibited by losartan and not by PD 123319. In agreement with these results, specific binding of 125I-[Sar1,Ile8]ANG II was markedly inhibited by losartan, whereas PD 123319 had no effect. These results demonstrate that AT1 receptor subtypes are present in intact rat proximal tubule cells and are coupled to both IPs-Ca2+ and cAMP signaling pathways. No evidence for AT2 receptor subtype is found.

scholarly journals Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II

2008 ◽  
Vol 295 (6) ◽  
pp. C1633-C1646 ◽  
Author(s):  
Gary E. Striker ◽  
Francoiçe Praddaude ◽  
Oscar Alcazar ◽  
Scott W. Cousins ◽  
Maria E. Marin-Castaño
Keyword(s):  
Extracellular Matrix ◽  
Angiotensin Ii ◽  
Type Iv Collagen ◽  
Pigment Epithelium ◽  
Receptor Expression ◽  
Age Related Macular Degeneration ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Type Iv

The early stage of age-related macular degeneration (AMD) is characterized by the formation of subretinal pigment epithelium (RPE) deposits as a result of the dysregulation in the turnover of extracellular matrix (ECM) molecules. However, the mechanism involved remains unclear. Hypertension (HTN) is an important risk factor for AMD, and angiotensin II (ANG II) is the most important hormone associated with HTN. However, the relevance of ANG II receptors and ANG II effects on RPE have not been investigated yet. Therefore, the expression and regulation of ANG II receptors as well as the ECM turnover were studied in human RPE. ANG II receptors were expressed and upregulated by ANG II in human RPE. This regulation resulted in functional receptor expression, since an increase in intracellular concentration of calcium was observed upon ANG II stimulation. ANG II also increased matrix metalloproteinase (MMP)-2 activity and MMP-14 at the mRNA and protein levels as well as type IV collagen degradation. These ANG II effects were abolished in the presence of the ANG II receptor subtype 1 (AT1) receptor antagonist candesartan. In contrast, ANG II decreased type IV collagen via both AT1 and AT2 receptors, suggesting a synergistic effect of the two receptor subtypes. In conclusion, we have confirmed the presence of ANG II receptors in human RPE and their regulation by ANG II as well as the regulation of ECM molecules via ANG II receptors. Our data support the hypothesis that ANG II may exert biological function in RPE through ANG II receptors and that ANG II may cause dysregulation of molecules that play a major role in the turnover of ECM in RPE basement membrane and Bruch's membrane, suggesting a pathogenic mechanism to explain the link between HTN and AMD.

Glomerular angiotensin II receptor subtypes during development of rat kidney

1993 ◽  
Vol 265 (2) ◽  
pp. F264-F271 ◽  
Author(s):  
G. M. Ciuffo ◽  
M. Viswanathan ◽  
A. M. Seltzer ◽  
K. Tsutsumi ◽  
J. M. Saavedra
Keyword(s):  
Angiotensin Ii ◽  
Kidney Development ◽  
Developmental Stages ◽  
Rat Kidney ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Kidney Medulla ◽  
At1 Receptors ◽  
Old Rats

We used quantitative autoradiography to investigate distribution of angiotensin II (ANG II) receptor subtypes during development of the kidney in the rat. In fetal, newborn, and 3-day-old rats, immature glomeruli in the form of comma and S-shaped bodies, located in the nephrogenic zone of the renal cortex, expressed only the angiotensin AT2 receptor subtype. Conversely, the juxtamedullary glomeruli, in more advanced developmental stages, expressed only the AT1 subtype. Similarly, maturing and fully developed glomeruli, present in 1-, 2-, and 8-wk-old rats, expressed only AT1 receptors. In the kidney medulla, there was a similar change in ANG II receptor subtype expression, with the AT2 subtype expressed earlier and the AT1 subtype later during development. Our results demonstrate a selective expression of ANG II receptor subtypes during kidney development. We have found glomerular and medullary AT1 receptors only at developmental stages when kidney function has matured. Conversely, AT2 receptors are expressed only in immature structures, suggesting that they may have a role during kidney organogenesis.

Angiotensin II-dependent proximal tubule sodium transport is mediated by cAMP modulation of phospholipase C

1994 ◽  
Vol 267 (5) ◽  
pp. C1239-C1245 ◽  
Author(s):  
J. R. Schelling ◽  
H. Singh ◽  
R. Marzec ◽  
S. L. Linas
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Adenylyl Cyclase ◽  
Phospholipase C ◽  
Sodium Transport ◽  
Cultured Cells ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Ang Ii ◽  
Sodium Flux

Angiotensin II (ANG II) stimulates proximal tubule sodium transport by decreasing adenylyl cyclase activity. The role of ANG II-dependent phospholipase C is less certain. To determine the contribution of phospholipase C and adenylyl cyclase to apical (AP) ANG II-dependent sodium transport, unidirectional (AP to basolateral) 22Na flux was measured in rat proximal tubule cells cultured on permeable supports. AP ANG II (100 nM)-dependent sodium flux was prevented by preincubation with concentrations of the phospholipase C inhibitor U-73122 (1 microM) that blocked ANG II-dependent inositol phosphate formation. AP ANG II-dependent sodium flux was also abolished by preincubation with the intracellular calcium mobilization inhibitor 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8), further suggesting that ANG II-dependent sodium transport was mediated by inositol phosphates. Neither U-73122 nor TMB-8 prevented ANG II-dependent adenosine 3',5'-cyclic monophosphate (cAMP) decreases. Incubation with dibutyryl cAMP (10 microM) or forskolin (10 microM) prevented ANG II-dependent sodium flux as well as ANG II-dependent inositol phosphate formation. In conclusion, ANG II-dependent proximal tubule sodium transport in cultured cells was transduced by phospholipase C and adenylyl cyclase. The adenylyl cyclase effect on ANG II-dependent sodium transport was mediated by phospholipase C.

Angiotensin II AT2 receptors inhibit growth responses in proximal tubule cells

2001 ◽  
Vol 281 (2) ◽  
pp. F300-F308 ◽  
Author(s):  
Joseph Zimpelmann ◽  
Kevin D. Burns
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Receptor Activation ◽  
Proximal Tubule Cell ◽  
Ang Ii ◽  
Phosphotyrosine Phosphatase ◽  
Proximal Tubule Cells ◽  
Transfected Cells ◽  
Mapk Activity ◽  
Tubule Cells

Angiotensin II (ANG II) subtype 2 (AT2) receptors are expressed in the adult kidney, but the effects of AT2 receptor activation are unclear. The proximal tubule cell line LLC-PK1 was transfected with a plasmid containing cDNA for the rat AT2 receptor. In transfected cells, specific binding of 125I-labeled ANG II was detected (dissociation constant = 0.81 nM), with inhibition by the AT2 antagonist PD-123319, and no effect of the AT1 antagonist losartan. ANG II (10−7 M) significantly inhibited mitogen-activated protein kinase (MAPK) activity in transfected cells, associated with decreased phosphorylation of the extracellular signal-related kinases ERK1 and ERK2. ANG II stimulated phosphotyrosine phosphatase activity within 5 min, an effect blocked by PD-123319 and the phosphatase inhibitor vanadate. In transfected cells, ANG II inhibited epidermal growth factor-stimulated [3H]thymidine incorporation, an effect reversed by vanadate. In contrast, vanadate did not block ANG II-stimulated apoptosis of transfected cells. In summary, AT2 receptors in proximal tubule cells inhibit MAPK activity and stimulate phosphotyrosine phosphatase. AT2receptor-induced inhibition of mitogenesis is mediated by phosphatase activation, whereas effects on apoptosis are insensitive to phosphatase inhibition. The data suggest that AT2 receptors inhibit cell growth via distinct signaling pathways in the proximal tubule.

scholarly journals Expression of type 1 angiotensin II receptor subtypes and angiotensin II-induced calcium mobilization along the rat nephron.

1997 ◽  
Vol 8 (11) ◽  
pp. 1658-1667 ◽  
Author(s):  
N Bouby ◽  
A Hus-Citharel ◽  
J Marchetti ◽  
L Bankir ◽  
P Corvol ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Collecting Duct ◽  
At1 Receptor ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Angiotensin Ii Receptor ◽  
Nephron Segments

The localization of two type 1 angiotensin II receptor subtype mRNA, AT1A and AT1B, was determined by reverse transcription-PCR on microdissected glomeruli and nephron segments. The coupling sensitivity of these two receptor subtypes was evaluated by measuring variations in intracellular calcium ([Ca2+]i) elicited by angiotensin II (Ang II) in structures expressing either AT1A or AT1B mRNA, using Fura-2 fluorescence. The highest expression of AT1 mRNA was found in glomerulus, proximal tubule, and thick ascending limb. In glomerulus, AT1A and AT1B mRNA were similarly expressed, whereas in all nephron segments AT1A mRNA expression was dominant (approximately 84%). The increase in [Ca2+]i elicited by 10(-7) mol/L Ang II was highest in proximal segments (delta [Ca2+]i is approximately equivalent to 300 to 400 nmol/L) and thick ascending limb (delta [Ca2+]i is approximately equivalent to 200 nmol/L). In glomerulus and collecting duct, the response was lower (delta < 100 nmol/L). The median effective concentrations for Ang II were of the same order of magnitude in glomerulus (12.2 nmol/L), in which both AT1A and AT1B are expressed, and in cortical thick ascending limb (10.3 nmol/ L), in which AT1A is almost exclusively expressed. The Ang II-induced calcium responses were totally abolished by the AT1 receptor antagonist losartan (1 mumol/L) but not by the AT2 antagonist PD 123319 (1 mumol/L). In the absence of external Ca2+, the peak phase of the response induced by 10(-7) mol/L Ang II was reduced and shortened, suggesting that a part of the [Ca2+]i increase originated from the mobilization of the intracellular Ca2+ pool. In conclusion, these results demonstrate that in the rat kidney: (1) AT1A is the predominant AT1 receptor subtype expressed in the nephron segments, (2) glomerulus is the only structure with a relatively high AT1B mRNA content, and (3) AT1A and AT1B receptor subtypes do not differ in their efficiency for the activation of calcium second-messenger system.

Tissue specific expression of vascular smooth muscle angiotensin II receptor subtypes during ovine pregnancy

1996 ◽  
Vol 271 (1) ◽  
pp. H212-H221 ◽  
Author(s):  
B. E. Cox ◽  
C. R. Rosenfeld ◽  
J. E. Kalinyak ◽  
R. R. Magness ◽  
P. W. Shaul
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Angiotensin Ii Receptor ◽  
Specific Expression ◽  
At1 Receptors ◽  
Mammary Arteries ◽  
At2 Receptors

Uteroplacentral responses to infused angiotensin II (ANG II) are less than those elicited by systemic vasculature. This does not reflect ANG II receptor (AT) downregulation but may reflect differences in AT-receptor subtypes expressed. We examined AT-receptor subtypes in smooth muscle (SM) from uterine (UA), mesenteric, renal, and mammary arteries and aorta from nulliparous (n = 12), pregnant (n = 18; 105-140 days, term = 145 days), postpartum (n = 5; 6-9 days after delivery), and nonpregnant parous (n = 14) ewes by assessing displacement of 125I-labeled ANG II binding by [Sar1, Ile8]ANG II (AT1 and AT2), losartan (AT1) PD-123319 (AT2), and CGP-42112A (AT2). AT2 receptors accounted for 75-90% of total binding in UA. Except for mammary arteries, other arteries expressed only AT1 receptors. Receptor subtype expression was not altered by reproductive state in any artery studied. With the use of autoradiography, AT2 receptors appear to predominate in media of small intramyometrial arteries, whereas AT1 receptors predominate in the luminal portion. We therefore determined which subtype mediates endothelium-derived ANG II-induced increases in UA PGI2 synthesis during pregnancy. ANG II (0.05 microM) increased PGI2 synthesis 62%, from 214 +/- 13 to 346 +/- 23 pg.mg-1.h-1 (P < 0.05). Losartan (1.0 microM) inhibited the rise in PGI2 (257 +/- 24 vs. 238 +/- 25 pg.mg-1.h-1), whereas 1.0 microM PD-123319 had no effect (231 +/- 23 vs. 337 +/- 31 pg.mg-1.h-1; P < 0.05). AT2 receptors do not mediate ANG II-induced vasoconstriction, thus differences in uteroplacental and systemic sensitivity to ANG II may reflect predominance of AT2 receptors in UASM and ANG II-induced increases in UA prostacyclin synthesis by endothelial AT1 receptors.

scholarly journals ANGIOTENSIN II (ANG II) MODULATES RESPONSE TO OXIDANT INJURY IN IMMORTALIZED RAT PROXIMAL TUBULE CELLS (IRPTC). † 2157

1996 ◽  
Vol 39 ◽  
pp. 362-362
Author(s):  
Julie R Ingelfinger ◽  
Liam Haveran ◽  
Dan Diamant ◽  
Flavia F Jung ◽  
Shiow-Shih Tang
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Ang Ii ◽  
Oxidant Injury ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Rat Proximal Tubule

scholarly journals Angiotensin II stimulation of Na+/K+ATPase activity and cell growth by calcium-independent pathway in MCF-7 breast cancer cells

2002 ◽  
Vol 173 (2) ◽  
pp. 315-323 ◽  
Author(s):  
A Muscella ◽  
S Greco ◽  
MG Elia ◽  
C Storelli ◽  
S Marsigliante
Keyword(s):  
Breast Cancer ◽  
Angiotensin Ii ◽  
Maximal Response ◽  
Epithelial Cell Line ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Ang Ii ◽  
At1 Antagonist ◽  
Mcf 7 ◽  
Stimulation Of

Here we demonstrated, by RT-PCR analysis, the expression of both angiotensin II (Ang II) receptor subtypes, AT1 and AT2, in a breast cancer epithelial cell line, MCF-7. Ang II was not able to affect the intracellular Ca2+ concentration in Fura-2 loaded cells suggesting that AT1-mediated phospholipid hydrolysis is not involved in its intracellular transduction pathway. Ang II modulated the activity of the Na+/K+ATPase in a dose- and time-dependent manner and was mitogenic, with a dose-dependent (1-1000 nM) proliferative effect and a maximal response at 100 nM. Both Na+/K+ATPase activation and stimulation of proliferation were mediated by binding of Ang II to AT1, as the effects were completely blocked by DuP 753, a specific AT1 antagonist. CGP 42112, an AT2 antagonist, did not affect Ang II actions. The main conclusion of this study is that Ang II exerts its effects on cell proliferation and Na+/K+ATPase in breast cancer epithelial cells, MCF-7, via AT1 activation independently of the Ca(2+) signalling mechanism.

The AT1A receptor “gain-of-function” mutant N111S/Δ329 is both constitutively active and hyperreactive to angiotensin II

2006 ◽  
Vol 290 (5) ◽  
pp. E840-E848 ◽  
Author(s):  
Sandrine Billet ◽  
Sabine Bardin ◽  
Rachida Tacine ◽  
Eric Clauser ◽  
Sophie Conchon
Keyword(s):  
Angiotensin Ii ◽  
Double Mutant ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Receptor Activation ◽  
Receptor Internalization ◽  
Renal Physiology ◽  
Ang Ii ◽  
Gain Of Function ◽  
Constitutively Active

The renin-angiotensin-aldosterone system (RAAS) is central to cardiovascular and renal physiology. However, there is no animal model in which the activation of the RAAS only reflects the activation of the angiotensin II (ANG II) AT1 receptor. As a first step to developing such a model, we characterized a gain-of-function mutant of the mouse AT1A receptor. This mutant carries two mutations: N111S predicted to activate the receptor constitutively and a COOH-terminal deletion, Δ329, expected to reduce receptor internalization and desensitization. We expressed this double mutant (AT1A-N111S/Δ329) in heterologous cells. It showed a pharmacological profile consistent with that of other constitutively active mutants. Furthermore, it increased basal production of inositol phosphates, as well as basal cytosolic and nuclear ERK activities. Basal proliferation of cells expressing the mutant was also greater than that of the wild type. The double mutant was poorly internalized and failed to recruit β-arrestin 2 in the presence of ANG II. It also showed hypersensitive and hyperreactive responses to ANG II for both inositol phosphate production and ERK activation. The additivity of the phenotypes of the two mutations makes this mutant an appropriate candidate to test the physiological consequences of the AT1A receptor activation itself in transgenic animal models.

Nephrogenesis and angiotensin II receptor subtypes gene expression in the fetal lamb

1998 ◽  
Vol 274 (6) ◽  
pp. F1062-F1069 ◽  
Author(s):  
Valérie Gimonet ◽  
Laurence Bussieres ◽  
Anissa A. Medjebeur ◽  
Bernard Gasser ◽  
Brigitte Lelongt ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mrna Expression ◽  
Mesangial Cells ◽  
Temporal Distribution ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Developmental Study ◽  
Ang Ii ◽  
Angiotensin Ii Receptor ◽  
Fetal Lamb

To investigate the role of angiotensin II (ANG II) in nephrogenesis, a developmental study of renal AT1 and AT2 receptor mRNA expression was performed in parallel with the quantitative and qualitative analysis of metanephros development in fetal lamb from 60 to 140 days of gestation. Both ANG II receptor subtypes were expressed early during nephrogenesis but displayed specific spatial and temporal distribution during gestation. High-AT2 mRNA expression took place in the outermost nephrogenic area and in the undifferentiated mesenchymal cells surrounding the ampulla; level of AT2 expression in this localization followed closely glomeruli proliferation rate and disappeared after nephrogenesis completion (>120 days). AT2 mRNA was also detected in the differentiated epithelial cells of macula densa of maturing glomeruli. Although most of AT1 mRNA labeling was found in the mesangial cells of maturing glomeruli, where it persisted after nephrogenesis completion, additional labeling was found in undifferentiated cells, in cells invading the inferior cleft of S-shaped bodies (80 days), and in medullar cells between tubules (120 days). Our results suggest that each receptor subtype has a specific role in renal morphogenesis, i.e., AT2 in mesenchymal proliferation or apoptosis and AT1 in vascular smooth muscle cells differentiation.

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