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)

Angiotensin II (ANG II) was shown to modulate transport in the renal proximal tubule through both inhibition of adenylate cyclase and protein kinase C (PKC) activation. We evaluated the effects of ANG II on adenosine 3',5'-cyclic monophosphate (cAMP) content and Na-H exchange activity (amiloride-sensitive Na influx) in two strains of opossum kidney (OK) cells originating from different sources, OK-VD and OK-RR cells. In OK-VD cells, ANG II inhibited basal and parathyroid hormone (PTH)-induced cAMP generation in a pertussis toxin-sensitive manner and reversed PTH inhibition of Na-H exchange. These effects of ANG II were prevented by PD 123319, a selective nonpeptide antagonist of AT2 receptors. In contrast, DuP 753, which antagonizes selectively AT1 receptors, had no effect. In OK-RR cells, ANG II had no effect on cAMP content and decreased Na-H exchange activity. The effect of ANG II persisted in the presence of PTH but was abolished by PKC downregulation and by DuP 753, but not by PD 123319. In conclusion, two types of ANG II receptors, coupled to distinct signaling pathways, were expressed independently in OK cells originating from two different sources and mediated opposite effects of ANG II on Na-H exchange activity. Those models provide a powerful tool for studying the intracellular steps involved in the tubular effects of ANG II and to evaluate the effect of pharmacological inhibitors of ANG II binding to its receptors.
 ...
PMID:Modulation of Na-H exchange activity by angiotensin II in opossum kidney cells. 133 86

1. From studies in chronically catheterized fetal sheep and other species, it can be shown that the renin-angiotensin system (RAS) is active during intra-uterine life. Levels of angiotensin II (AII) in fetal sheep are similar to maternal. 2. The fetal RAS plays a role in maintenance of arterial pressure. The extent to which it does so depends on the level of activity of the system. 3. The distribution of renin within the fetal rat kidney is much more widespread than in the adult. The fetal kidney, like other vascular beds has high levels of the AT2 angiotensin receptor subtype. With maturation the proportion of the AT1 receptor subtype increases. 4. Blockade of the fetal RAS with angiotensin converting enzyme (ACE) inhibitors or with the non-peptide AII antagonist (losartan) caused a fall in fetal glomerular filtration rate (GFR) and a rise in renal blood flow (RBF). AII reverses the fall in GFR even though RBF decreases. 5. The fraction of the filtered sodium load reabsorbed by the proximal tubule was not affected when the fetal RAS was blocked by captopril or losartan. High doses of infused AII had no effect on renal reabsorption of sodium, in the short term, but in the long term depressed fractional proximal reabsorption. 6. Only in high doses does AII stimulate the secretion of aldosterone from the fetal adrenal.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Functions of the renin-angiotensin system during development. 758 4

Angiotensin II (ANG II) receptors of the AT1 subtype are present on the apical and basolateral membranes of renal proximal tubule cells. Cells of the proximal tubulelike cell line, LLC-PK1/Cl4, were transfected with an expression plasmid containing cDNA encoding the rabbit AT1 ANG II receptor. In transfected cells, specific binding of 125I-ANG II was detected on both apical and basolateral membranes; wild-type LLC-PK1/Cl4 cells did not express ANG II receptors. In transfected cells, apical or basolateral ANG II increased both S6 kinase activity and incorporation of [3H]leucine. In cells pretreated with pertussis toxin, the stimulatory effect of apical or basolateral ANG II on [3H]leucine incorporation was abolished. In contrast, ANG II did not affect mitogenesis, determined by [3H]thymidine incorporation. Apical or basolateral ANG II (10(-6) M) stimulated phosphoinositide turnover by 13.4 +/- 4.4% (n = 8) and 16.3 +/- 4.2% (n = 9), respectively. The activity of protein kinase C, determined by phosphorylation of a specific protein kinase C peptide substrate, was also stimulated by ANG II in transfected cells. Apical or basolateral ANG II had no significant effect on cellular adenosine 3',5'-cyclic monophosphate levels. In permeabilized transfected cells, apical ANG II (10(-6) M) inhibited the phosphorylation of a specific peptide substrate of protein kinase A; lower apical concentrations or basolateral ANG II were without significant effect. These results indicate that AT1 ANG II receptors sort to both apical and basolateral membranes in renal epithelial cells and are coupled to activation of phospholipase C. ANG II stimulates protein synthesis by binding to either apical or basolateral receptors; this effect requires coupling to G proteins and may be mediated by activation of S6 kinase. Because high concentrations of ANG II exist in proximal tubule, binding to apical and basolateral receptors may regulate proximal tubule cell growth under physiological conditions.
 ...
PMID:Signaling and growth responses of LLC-PK1/Cl4 cells transfected with the rabbit AT1 ANG II receptor. 773 40

Angiotensin II (Ang II) is an important regulator of proximal tubule salt and water reabsorption. Recent studies indicate that rabbit proximal tubule angiotensin II receptors are the type-1 (AT1R) subtype. We studied the effect of Ang II on proximal tubule receptor expression. Rabbits were treated with either angiotensin converting enzyme inhibitors or a low salt diet to modulate endogenous Ang II levels. In captopril-treated rabbits, liver and glomerular AT1R mRNA levels increased 242 +/- 125 and 141 +/- 60%, respectively (n = 6-7; P < 0.05), as determined by quantitative PCR. In contrast, proximal tubule AT1R mRNA levels decreased 40 +/- 11% (n = 6; P < 0.05). Binding of 125I Ang II to renal cortical basolateral membranes of captopril-treated rabbits decreased from 2.9 +/- 0.55 to 1.4 +/- 0.17 fmol/mg protein (n = 6; P < 0.025). In rabbits fed a sodium chloride-deficient diet for 4 wk, AT1R mRNA levels decreased 52 +/- 11% in liver and 43 +/- 7% in glomeruli (n = 4-5; P < 0.05), whereas they increased 141 +/- 85% (n = 5; P < 0.05) in proximal tubule. In basolateral membranes from rabbits on the sodium chloride-deficient diet, specific binding of 125I Ang II increased from 2.1 +/- 0.2 to 4.3 +/- 1.1 fmol/mg protein (n = 7; P < 0.05). To determine whether Ang II directly regulates expression of proximal tubule AT1 receptors, further studies were performed in cultured proximal tubule cells grown from microdissected S1 segments of rabbit proximal tubules and immortalized by transfection with a replication-defective SV40 vector. Incubation of these cells with Ang II (10(-11) to 10(-7) M) led to concentration-dependent increases in both AT1R mRNA levels and specific 125I Ang II binding. Pretreatment with pertussis toxin inhibited Ang II stimulation of AT1R mRNA. AT1R mRNA expression was decreased by either forskolin or a nonhydrolyzable cAMP analogue (dibutryl cAMP). Simultaneous Ang II administration overcame the inhibitory effect of forskolin but not dibutryl cAMP. These results indicate that proximal tubule AT1R expression is regulated by ambient Ang II levels, and Ang II increases AT1R mRNA at least in part by decreasing proximal tubule cAMP generation through a pertussis toxin-sensitive mechanism. Upregulation of proximal tubule AT1R by Ang II may be important in mediating enhanced proximal tubule sodium reabsorption in states of elevated systemic or intrarenal Ang II.
 ...
PMID:Angiotensin II upregulates type-1 angiotensin II receptors in renal proximal tubule. 773 68

Angiotensin II (ANG II) plays an important role in the regulation of solute transport in the kidney, and its effect on proximal tubule sodium and fluid transport has been studied extensively. Although there is evidence that ANG II receptors are present also in the distal nephron and collecting duct, little is known about the physiological role of ANG II in these segments of the renal tubule. Preliminary studies in our laboratory suggest that ANG II may have both structural and functional effects on intercalated cells in the cortical collecting duct (CCD). Therefore, the present study examines the effect of ANG II on H(+)-adenosinetriphosphatase (H(+)-ATPase) and H(+)-K(+)-ATPase activity in individual CCD segments microdissected from collagenase-treated rat kidneys. The H(+)-ATPase was measured as bafilomycin-sensitive ATPase activity, and H(+)-K(+)-ATPase was measured as Sch-28080-sensitive ATPase activity, by a fluorometric microassay. Preincubation of CCD segments with ANG II, 10(-10)-10(-5) M, caused a dose-dependent decrease in H(+)-ATPase activity with maximum inhibition at 10(-8) M of ANG II. The inhibitory effect of ANG II was abolished when tubules were incubated with ANG II in the presence of 10(-6) M losartan, indicating that the inhibition was mediated via specific AT1 receptors. The AT2-receptor antagonist, PD-123319, had no effect on the ANG II-mediated inhibition of H(+)-ATPase activity. Preincubation of CCD segments with 10(-10) or 10(-7) M ANG II had no effect on H(+)-K(+)-ATPase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Angiotensin II regulates H(+)-ATPase activity in rat cortical collecting duct. 781 Jun 90

The effect of angiotensin 1-7 (Ang 1-7) on the proximal tubule has not been well studied. It was hypothesized that Ang 1-7 has a biphasic effect on fluid absorption in the isolated rat proximal straight tubule. Proximal straight tubules were perfused at a rate of 5.81 +/- 0.44 nL/mm per minute and absorbed fluid at 0.98 +/- 0.10 nL/mm per minute. Bicarbonate absorption was 80.1 +/- 11.6 pmol/mm per minute. When 10(-12) M Ang 1-7 was added to the bath, fluid absorption increased to 1.47 +/- 0.10 nL/mm per minute (P < 0.013) and bicarbonate increased to 115.0 +/- 12.8 pmol/mm per minute (P < 0.004). Ang 1-7 had no effect on either the maximum rate of bicarbonate absorption (P > 0.90) or bicarbonate permeability (P > 0.60). Next, 10(-8) M Ang 1-7 was used. During the control period, fluid absorption was 0.90 +/- 0.09 nL/mm per minute. When 10(-8) M Ang 1-7 was added, fluid absorption decreased to 0.62 +/- 0.04 nL/mm per minute (P < 0.05). DuP 753, an AT1 receptor antagonist, blocked both effects induced by Ang 1-7, whereas PD 123319, an AT2 receptor antagonist, did not block the stimulatory effect. From these data, it was concluded that Ang 1-7 binds AT1 receptors and has a biphasic effect on fluid absorption, and at physiologic levels, the heptapeptide induces the stimulation of bicarbonate absorption.
 ...
PMID:Angiotensin 1-7 has a biphasic effect on fluid absorption in the proximal straight tubule. 784 54

Immortalized rat proximal tubule cell (IRPTC) lines should be useful for investigation of proximal tubule (PT) regulation and function but previously have been unavailable. We now report the establishment and characterization of an immortalized transformed, temperature-sensitive IRPTC cell line containing renin-angiotensin system (RAS) components. Primary PT cells prepared from male Wistar rats (4-5 wk old) after collagenase digestion, sieving, and Percoll gradient were cultured on collagen-coated T-75 flasks in Dulbecco's modified Eagle's medium containing 5% fetal calf serum. Subconfluent PT cells were transfected with the temperature-sensitive SV40 mutant viruses (tsA SV40) by direct exposure. After 7-8 wk, several clones were obtained, from which one has been characterized and designated as line 3-2. This cell line appears stable up to 45 passages. Clonal cells transformed with this virus exhibit a transformed phenotype at a permissive temperature of 34 degrees C and grow in multiple layers. When the cells are subsequently placed at a nonpermissive temperature of 41 degrees C, they return to morphology similar to that of untransformed cells of the same lineage. At either 34 degrees C or 41 degrees C, this cell line expresses a variety of PT markers including alkaline phosphatase, cytokeratin, carbonic anhydrase, and glucose transporter isoform 2 (GLUT2), while not expressing factor VIII. Uniquely, these cells also appear to express PT proteins gp330 and CHIP28, markers which are usually lost in cultured cells. Furthermore, the cell line expresses protein and mRNA components of RAS, including angiotensinogen, angiotensin converting enzyme, and renin. The IRPTC cell line expresses few angiotensin II (ANG II) receptors at 34 degrees C, the permissive temperature. However, at the nonpermissive temperature, 41 degrees C, IRPTC expresses ANG II receptor (dissociation constant of 0.7 nM; maximum binding capacity of 265 fmol/mg protein). ANG II (10(-8) M) induced a transient rise in cytoplasmic Ca2+ concentration, which was nearly abolished with losartan but not PD-123319, suggesting this finding is AT1 receptor mediated. This cell line should provide an excellent model of PT and should make it possible to study the cell and molecular biology of the RAS, as well as other regulatory systems of the PT.
 ...
PMID:Temperature-sensitive SV40 immortalized rat proximal tubule cell line has functional renin-angiotensin system. 790 Aug 43

The rabbit proximal tubule (PT) has been widely utilized to study the direct effects of angiotensin II (ANG II) on PT function. The purpose of the present study was to characterize the binding properties of PT ANG II receptors, using nonpeptide antagonists, and to clone a rabbit PT ANG II receptor. In rat and rabbit kidney cortical brush-border and basolateral membranes, specific binding of 125I-ANG II was inhibited by the AT1 ANG II-receptor antagonist DuP 753, but not by the AT2 antagonist PD 123319. Using a rabbit kidney cortex cDNA library, we isolated cDNA encoding an ANG II receptor, with an open-reading frame sharing a high degree of sequence homology to previously cloned AT1 ANG II receptors. In transfected COS-1 cells, this rabbit ANG II receptor had properties of the AT1 class. Northern analysis revealed high levels of mRNA expression for this receptor in rabbit kidney cortex and adrenal gland. Within the kidney, message was detected in primary cultures of rabbit PT cells, as well as in freshly isolated rabbit PT segments. Message was also present in cells of the mouse PT line, MCT, and in rat glomerular mesangial cells. Utilizing polymerase chain reaction (PCR) with primers derived from the 1st and 4th transmembrane domains of the rat AT1A ANG II receptor, a 279-bp DNA fragment was amplified from reverse-transcribed RNA from rabbit PT cells. This DNA encoded an amino acid sequence identical to that encoded by the rabbit kidney cDNA clone in the corresponding region and differed by a single base substitution. Southern analysis of rabbit genomic DNA restriction digests with the rabbit ANG II receptor probe revealed hybridization to a single band in each lane. These results indicate that an AT1 ANG II receptor is present in the PT and that a single gene codes for the AT1 receptor in rabbit. The clone isolated in the present study should provide a useful tool with which to study the regulation of the PT renin-angiotensin system.
 ...
PMID:Cloning of a rabbit kidney cortex AT1 angiotensin II receptor that is present in proximal tubule epithelium. 791 79

Angiotensin II has been reported to stimulate the proximal tubule Na-H antiporter by inhibition of adenylyl cyclase, and possibly by an adenosine 3',5'-cyclic monophosphate (cAMP)-independent mechanism. We examined the effect of angiotensin II on Na-H antiporter activity (JNa-H) in opossum kidney (OKP) cells, a proximal tubule-like cell line, whose Na-H antiporter resembles that of the proximal tubule apical membrane. We found that angiotensin II regulates JNa-H in a concentration-dependent manner similar to the proximal tubule, with angiotensin II concentrations < 10(-8) M stimulating and > 10(-8) M inhibiting JNa-H. The stimulatory effect of angiotensin II was blocked by 10(-8) M losartan and was pertussis toxin sensitive, suggesting mediation through an angiotensin II (AT1) receptor coupled to a pertussis toxin-sensitive G protein. Acute treatment with 10(-4) M 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) inhibited JNa-H by 30% and blocked angiotensin II-induced stimulation. However, angiotensin II (10(-12)-10(-6) M) did not inhibit basal, dopamine-stimulated, or forskolin-stimulated cAMP production measured in the presence of 3-isobutyl-1-methylxanthine (IBMX). In addition, angiotensin II had no effect on cAMP levels measured in the absence of IBMX. We conclude that angiotensin II at physiological concentrations stimulates JNa-H in OKP cells via a cAMP-independent mechanism mediated by an AT1 receptor and a pertussis toxin-sensitive G protein.
 ...
PMID:Angiotensin II stimulation of Na-H antiporter activity is cAMP independent in OKP cells. 802 91

Angiotensin II (ANG II) receptors are present on apical and basolateral surfaces of proximal tubule cells. To determine the cellular mechanisms of proximal tubule ANG II receptor-mediated Na transport, apical-to-basolateral 22Na flux was measured in cultured proximal tubule cells. Apical ANG II caused increases in 22Na flux (maximum response: 100 nM, 30 min). Basolateral ANG II resulted in 22Na flux that was 23-56% greater than 22Na flux observed with equimolar apical ANG II. Apical ANG II-induced 22Na flux was prevented by preincubation with amiloride, ouabain, and the AT1 receptor antagonist losartan. Because apical ANG II signaling was previously shown to be endocytosis dependent, we questioned whether endocytosis was required for ANG II-stimulated proximal tubule Na transport as well. Apical (but not basolateral) ANG II-dependent 22Na flux was inhibited by phenylarsine oxide, an agent which prevents ANG II receptor internalization. In conclusion, apical and basolateral ANG II caused proximal tubule Na transport. Apical ANG II-dependent Na flux was mediated by AT1 receptors, transcellular transport pathways, and receptor-mediated endocytosis.
 ...
PMID:Angiotensin II-dependent proximal tubule sodium transport requires receptor-mediated endocytosis. 816 30


1 2 3 4 5 6 7 8 Next >>