Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies revealed that angiotensin II (Ang II) interacts with two pharmacologically different subtypes of cell surface receptors. Type I Ang II (AT1) receptor is characterized by signal transduction mediated through G protein and phospholipase C. In this study, the micro-localization of mRNAs coding for AT1 receptor and angiotensinogen was carried out in the rat kidney, using an assay of reverse transcription and polymerase chain reaction (RT-PCR) in individual microdissected renal tubule segments along the nephron, glomeruli, vasa recta bundle, and arcuate arteries. Large signals for AT1 receptor were detected in the glomerulus, proximal convoluted tubule (PCT), proximal straight tubule (PST), cortical collecting duct, and vascular system. Small signals were also seen in medullary thick ascending limb, outer medullary collecting duct, and inner medullary collecting duct (IMCD). Angiotensinogen mRNA is expressed largely in PCT, PST, and a small amount in glomerulus and vasa recta. Our data demonstrate that Ang II could be produced locally in proximal tubule and vasa recta bundle, and that the AT1 receptor was widely distributed not only in the glomerulus and vessels but also in tubules from PCT to IMCD.
 ...
PMID:PCR localization of angiotensin II receptor and angiotensinogen mRNAs in rat kidney. 831 39

Angiotensin II (Ang II) is a potent regulator of proximal tubule functions, including transport, metabolism, and cell proliferation. The opossum kidney (OK) cell line is a useful model of renal proximal tubule. Mitogen-activated protein (MAP) kinases are rapidly phosphorylated and activated in response to various agonists. We investigated Ang II effects on serine/threonine kinase cascades in OK cells. The major findings of the present study are that Ang II stimulated MAP kinase kinase (MAPKK), MAP kinase (MAPK), and S6 kinase activities, and that it increased phosphorylation of Raf-1 kinase and p42 MAP kinase in OK cells. These stimulations of kinases were dose-dependent (from 10(-6) to 10(-11) M). The time course of activation was sequential; the peak stimulation was reached at 5 to 10 minutes for Raf-1 kinase, MAPKK and MAPK, and at 20 minutes for S6 kinase. The activation of MAPK was inhibited by approximately 70% with prolonged 24-hour PMA pretreatment or in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein and herbimycin) did not inhibit AngII-induced MAPK activity. This activation of MAPK was also inhibited via AT1 receptor antagonist, Dup753 and pertussis toxin. This evidence suggests that the activation of serine/threonine cascades by Ang II is largely dependent on PMA-sensitive PKC, and is not dependent on tyrosine kinase and pertussis toxin.
 ...
PMID:Sequential activation of MAP kinase cascade by angiotensin II in opossum kidney cells. 858 39

Systemic and/or locally produced angiotensin II stimulates salt and water reabsorption in the renal proximal tubule. In vivo, dopamine (DA) may serve as a counterregulatory hormone to angiotensin II's acute actions on the proximal tubule. We examined whether dopamine modulates AT1 receptor expression in cultured proximal tubule cells (RPTC) expressing DA1 receptors. Dopamine decreased basal RPTC AT1 receptor mRNA levels by 67 +/- 7% (n = 10; P < 0.005) and decreased 125I-angiotensin II binding by 41 +/- 7% (n = 4; P < 0.05). The DA1-specific agonist, SKF38393 decreased basal AT1 receptor mRNA levels (65 +/- 5% inhibition; n = 5; P < 0.025), and the DA1-specific antagonist, SCH23390 reversed dopamine's inhibition of AT1 receptor mRNA expression (24 +/- 10% inhibition; n = 8; NS) and angiotensin II binding (5 +/- 15%; n = 4; NS). DA2-specific antagonists were ineffective. In rats given L-DOPA in the drinking water for 5 d, there were decreases in both proximal tubule AT1 receptor mRNA expression (80 +/- 5%; n = 6; P < 0.005) and specific [125I] Ang II binding (control: 0.74 +/- 0.13 fmol/mg pro vs. 0.40 +/- 0.63 fmol/mg pro; n = 5; P < 0.05). In summary, dopamine, acting through DA1 receptors, decreased AT1 receptor expression in proximal tubule, an effect likely mediated by increased intracellular cAMP levels. Local dopamine production also led to decreased AT1 receptor expression, suggesting dopamine may reset sensitivity of the proximal tubule to angiotensin II.
 ...
PMID:Dopamine decreases expression of type-1 angiotensin II receptors in renal proximal tubule. 867 85

Several new non-peptide, orally active, angiotensin II receptor antagonists have recently been developed which enable to block the renin-angiotensin system at the AT1 receptor site. In contrast to angiotensin converting enzyme (ACE) inhibitors, these antagonists do not interfere with the metabolism of kinins. The effect of these agents on renal function may thus potentially differ from those of ACE inhibitors. Therefore, the renal pharmacology of various angiotensin II receptor antagonists has been examined in normotensive subjects. In normotensive subjects, losartan and irbesartan have been shown to have no effect on glomerular filtration rate and to induce either no change or a modest increase in renal blood flow. These results were confirmed thereafter in hypertensive patients where losartan produced a renal vasodilation with no change in glomerular filtration. In healthy subjects, both losartan and irbesartan induce an acute increase in urinary sodium excretion. The natriuretic response to losartan is proportionally more important during salt-depletion. In contrast to other angiotensin II receptor antagonists, losartan has a unique property to increase uric acid excretion. In this paper we show that this property is due to the potent inhibitory effect of the parent compound of losartan on the urate/anion transport in the human renal proximal tubule.
 ...
PMID:Renal effects of angiotensin II receptor blockade in normotensive subjects. 874 98

In vivo studies were conducted in Na-replete anesthetized male Wistar rats with denervated kidneys. Intrarenal injections of angiotensin-(1-7) [ANG-(1-7) at > 1 nmol/kg produced a shallow dose-dependent decrease in renal blood flow that was mediated by the AT1-type ANG II receptor. A constant intrarenal infusion of ANG-(1-7) at 0.1 and 1 nmol.min-1.kg-1 had minimal effects on renal blood flow and blood pressure and resulted in an elevated urinary excretion of Na and water compared with the time-control saline-infused group. To determine whether ANG-(1-7) may have a direct action on tubular epithelium to inhibit Na reabsorption, we examined the effect of ANG-(1-7) on transport-dependent O2 consumption (Qo2) in fresh suspensions of rat proximal tubules in vitro. ANG-(1-7) inhibited Qo2 in a concentration-dependent fashion with a threshold concentration of approximately 100 pM. Stimulating Na-K-adenosinetriphosphatase (Na-K-ATPase) activity with nystatin caused a leftward shift of the inhibitory concentration-response curve to ANG-(1-7). The 22% inhibition of Qo2 by 1 pM ANG-(1-7) was abolished by pretreatment with 5 mM ouabain (Na-K-ATPase inhibitor), unaltered by pretreatment with 1 microM PD-123319 (AT2 receptor antagonist), partially attenuated by 1 microM losartan (AT1 receptor antagonist), and abolished by 1 microM [Sar1, Thr8]ANG II (nonselective ANG receptor antagonist). Together these findings indicate that ANG-(1-7) has biological activity in the kidney and, at nonvasoconstrictor doses, results in increased Na and water excretion in vivo. One site of action is the proximal tubule, where ANG-(1-7) can inhibit an ouabain-sensitive Na-K-ATPase exit step in cellular Na transport. This novel inhibitory action of ANG-(1-7) appears to be mediated by an AT1 receptor (minor component) and a non-AT1, non-AT2 ANG receptor (major component).
 ...
PMID:Renal actions of angiotensin-(1-7): in vivo and in vitro studies. 876 32

We have developed chimeric mice carrying 'regional' null mutation of the angiotensin type 1A (AT1A) receptor, the AT1 receptor subtype exclusively present in mouse juxtaglomerular (JG) cells. The chimeric mouse (Agtr1a -/- <--> +/+) is made up of wild-type (Agtr1a +/+) cells or cells homozygous for Agtr1a deletion (Agtr1a -/-). In the latter, the AT1A coding exon was replaced with a reporter gene, lacZ. In Agtr1a -/- <--> +/+ mice, these two clones of cells are found to be clustered and display patchy distributions in the kidney and heart. Tracking of lacZ activities in hetero- (Agtr1a +/-) and homozygous (Agtr1a -/-) deletion mutant offspring from Agtr1a -/- <--> +/+ mice revealed that the promoter activity of Agtr1a is localized in JG cells, afferent arteriolar walls, glomerular mesangial region and endothelial cells, and apical and basolateral proximal tubule membranes. The JG apparatuses of Agtr1a -/- mice are markedly enlarged with intense expression of renin mRNA and protein. In Agtr1a -/- <--> +/+ mice, these changes were proportional to the degree of chimerism. Within a given Agtr1a -/- <--> +/+ mouse, however, the degree of JG hypertrophy/hyperplasia and the expression of renin mRNA and protein were identical between Agtr1a +/+ and Agtr1a -/- cells. Thus, in the in vivo condition tested, the local interaction between angiotensin and the AT1 receptor on the JG cells has little functional contribution to the feedback regulation of JG renin synthesis.
 ...
PMID:Chimeric mice carrying 'regional' targeted deletion of the angiotensin type 1A receptor gene. Evidence against the role for local angiotensin in the in vivo feedback regulation of renin synthesis in juxtaglomerular cells. 887 39

Because angiotensin II (Ang II) has been found at high concentrations in the proximal tubule fluid and because tubular brush border membranes exhibit a marked capacity for degrading Ang II, we thought it of interest to examine the binding sites for Ang II (3-8) (referred to as Ang IV), a metabolite of Ang II, downstream in the nephron. We studied the binding of [125I]-Ang IV and also of [125I]-Sar1, Ala8, Ang II to SV-40 transformed human collecting duct cell (HCD) membranes. No specific binding site for [125I]-Sar1, Ala8, Ang II and no Ang II-dependent cytosolic calcium response could be observed. Moreover, no signal for the human type I Ang II receptor (hAT1) mRNA was present in HCD cells. In contrast, [125I]-Ang IV bound specifically to HCD cell membranes. Mean Kd and Bmax values derived from saturation binding studies were 5.6 +/- 2.0 nM and 1007.6 +/- 140.2 fmol/mg protein, respectively. The rank order of affinity for competitive Ang II-related peptides was: Ang IV > Ang III > Ang II > Ang II (4-8) > Ang II (1-7). [125I]-Ang IV binding was not modified by nonpeptide AT1 (losartan) or AT2 (PD123177) antagonists. GTP gamma S and dithiotreitol did not affect [125I]-Ang IV binding. Ang IV stimulated cAMP production by intact HCD cells in the presence of forskolin but did not modify cGMP production or cytosolic calcium concentration. Taken together, these results indicate that HCD cells represent a target site for Ang IV but do not possess Ang II receptors.
 ...
PMID:Evidence for angiotensin IV receptors in human collecting duct cells. 888 69

1. The effects of angiotensin II (AngII) on water and electrolyte transport are biphasic and dose-dependent, such that low concentrations (10(-12) to 10(-9) mol/L) stimulate reabsorption and high concentrations (10(-7) to 10(-6) mol/L) inhibit reabsorption. Similar dose-response relationships have been obtained for luminal and peritubular addition of AngII. 2. The cellular responses to AngII are mediated via AT1 receptors coupled via G-regulatory proteins to several possible signal transduction pathways. These include the inhibition of adenylyl cyclase, activation of phospholipases A2, C or D and Ca2+ release in response to inositol-1,4,5,-triphosphate or following Ca2+ channel opening induced by the arachidonic acid metabolite 5,6,-epoxy-eicosatrienoic acid. In the brush border membrane, transduction of the AngII signal involves phospholipase A2, but does not require second messengers. 3. Angiotensin II affects transepithelial sodium transport by modulation of Na+/H+ exchange at the luminal membrane and Na+/HCO3 cotransport, Na+/K(+)-ATPase activity and K+ conductance at the basolateral membrane. 4. Atrial natriuretic factor (ANF) does not appear to affect proximal tubular sodium transport directly, but acts via specific receptors on the basolateral and brush border membranes to raise intracellular cGMP levels and inhibit AngII-stimulated transport. 5. It is concluded that there is a receptor-mediated action of ANF on proximal tubule reabsorption acting via elevation of cGMP to inhibit AngII-stimulated sodium transport. This effect is exerted by peptides delivered at both luminal and peritubular sides of the epithelium and provides a basis for the modulation by ANF of proximal glomerulotubular balance. The evidence reviewed supports the concept that in the proximal tubule, AngII and ANF act antagonistically in their roles as regulators of extracellular fluid volume.
 ...
PMID:Regulation of renal tubular sodium transport by angiotensin II and atrial natriuretic factor. 899 49

Molecular and functional studies have suggested that AT1 receptors are present in most nephron segments, yet direct demonstration of AT1 at these sites is lacking. The present study was performed to determine the intrarenal localization of the AT1 receptor utilizing a monoclonal anti-peptide (amino acid residues 8-17) antibody (6313/G2) in adult male Sprague-Dawley rats. Western blot analysis of kidney protein extracts showed a predominant 41-kDa immunoreactive band corresponding to the molecular weight of the deduced cDNA sequence. To determine optimal fixation conditions, kidney tissues were immersion fixed in Bouin's solution, 10% buffered Formalin, or 4% paraformaldehyde. Specificity of immunostaining was documented by preadsorption of the antibody with the immunogenic peptide sequence. Prominent AT1 immunostaining was visualized in the proximal tubule brush-border and basolateral membranes. In addition, distal tubules, cortical and medullary collecting ducts, and the renal arterial vasculature exhibited specific immunoreactivity. Glomerular staining for AT1 was observed in mesangial cells and podocytes. Macula densa cells stained positively. Similar localization of the AT1 receptor was obtained using the three tissue fixation methods, although the intensity of vascular and glomerular staining was highest in Bouin-fixed tissues. The present study demonstrates that the AT1 receptor is more widely distributed along the nephron than previously described and includes renal vascular smooth muscle and proximal and distal epithelial sites.
 ...
PMID:Immunohistochemical localization of ANG II AT1 receptor in adult rat kidney using a monoclonal antibody. 924 5

In order to examine the effects and the interaction of angiotensin II (ANG II, 1 pM) and atrial natriuretic peptide (ANP, 1 microM) on the kinetics of bicarbonate reabsorption in the rat middle proximal tubule, we performed in vivo experiments using a stopped-flow microperfusion technique with the determination of lumen pH by Sb microelectrodes. These studies confirmed that ANG II added to the luminal or peritubular capillary perfusion fluid stimulates proximal bicarbonate reabsorption and showed that ANP alone does not affect this process, but impairs the stimulation caused by ANG II. We also studied the effects and the interaction of these hormones in cortical distal nephron acidification. Bicarbonate reabsorption was evaluated by the acidification kinetic technique in early (ED) and late (LD) distal tubules in rats during in vivo stopped-flow microperfusion experiments. The intratubular pH was measured with a double-barreled microelectrode with H(+)-sensitive resin. The results indicate that ANG II acted by stimulating Na+/H+ exchange in ED (81%) and LD (54%) segments via activation of AT1 receptors, as well as vacuolar H(+)-ATPase in LD segments (33%). ANP did not affect bicarbonate reabsorption in either segment and, as opposed to what was seen in the proximal tubule, did not impair the stimulation caused by ANG II. To investigate the mechanism of action of these hormones in more detail, we studied cell pH dependence on ANG II and ANP in MDCK cells using the fluorescent probe BCECF. We showed that the velocity of cell pH recovery was almost abolished in the absence of Na+, indicating that it is dependent on Na+/H+ exchange. ANP (1 microM) alone had no effect on this recovery but reversed both the acceleration of H+ extrusion at low ANG II levels (1 pM and 1 nM), and inhibition of H+ extrusion at higher ANG II levels (100 nM). To obtain more information on the mechanism of interaction of these hormones, we also studied their effects on the regulation of intracellular free calcium concentration, [Ca2+]i, monitored with the fluorescent probe Fura-2 in MDCK cells in suspension. The data indicate that the addition of increasing concentrations of ANG II (1 pM to 1 microM) to the cell suspension led to a progressive increase in [Ca2+]i to 2-3 times the basal level. In contrast, the addition of ANP (1 microM) to the cell suspension led to a very rapid 60% decrease in [Ca2+]i and reduced the increase elicited by ANG II, thus modulating the effect of ANG II on [Ca2+]i. These results may indicate a role of [Ca2+]i in the regulation of the H+ extrusion process mediated by Na+/H+ exchange and stimulated/impaired by ANG II. The data are compatible with stimulation of Na+/H+ exchange by increases of [Ca2+]i in the lower range, and inhibition at high [Ca2+]i levels.
 ...
PMID:Interactions of ANP and ANG II in tubular nephron acidification. 925 67


<< Previous 1 2 3 4 5 6 7 8 Next >>