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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular processes leading to renal tubular hypertrophy may contribute to the development of progressive renal disease. Angiotensin II (ANG II) is a prime agent that has been linked to the progression of renal disease by a host of mechanisms, including the induction of tubular epithelial hypertrophy and stimulation of extracellular matrix biosynthesis. All components of a functional renin-angiotensin system reside within the renal tubule. Epithelial cells exhibit distinct patterns of growth behavior after stimulation with ANG II (namely, hypertrophy of proximal tubule segments and proliferation of more distal segments). The hypertrophic action of ANG II is mediated through high-affinity AT1-receptors, involves activation of pertussis-toxin sensitive G1 proteins, and depends on a decrease in intracellular cAMP. In addition, ANG II induces sequential activation of MAP kinases and S6 kinase, and leads to activation of early immediate genes and the modulation of a series of cyclins and cyclin-dependent kinases. There is also compelling evidence that the ANG II-induced epithelial hypertrophy and the stimulated-synthesis of collagen type IV are mediated by increased transcription and production of TGF-beta. ANG II-mediated inhibition of protein degradation may further increase protein content. The hypertrophic response to ANG II is greater in medium with high glucose concentration. Blockade of the action of ANG II prevents the renal hypertrophy and the tubulointerstitial fibrosis in animal models of chronic renal diseases (independent of changes in systemic or glomerular hemodynamics), in part through interception of ANG II-mediated induction of TGF-beta expression.
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PMID:Renal tubular hypertrophy induced by angiotensin II. 931 13

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.
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PMID:Expression of type 1 angiotensin II receptor subtypes and angiotensin II-induced calcium mobilization along the rat nephron. 935 68

Dietary potassium (K+) deficiency is associated with blood pressure elevation and impaired urinary sodium excretion. Since angiotensin II is a potent stimulator of tubular sodium transport, we studied the effect of low [K+] on expression of kidney AT1 angiotensin receptors. In rabbits fed a K+-deficient diet for 14 days, plasma [K+] was significantly reduced compared to rabbits fed a standard diet (control: 4.06 +/- 0.12 vs. K+-deficient: 2.66 +/- 0.19 mmol/l; p < 0.001; n = 6-9). By Northern hybridization or RNase protection assays, dietary K+ deficiency caused an increase in mRNA expression for AT1 receptors in kidney cortex (43.5 +/- 12.9% increase vs. control; p < 0.04; n = 8), and in proximal tubule segments in suspension (76.4 +/- 28.8% increase vs. control; p < 0.005; n = 6). K+ deficiency had no effect on AT1 receptor mRNA expression in liver, or on mRNA expression of beta-actin in kidney cortex, proximal tubule suspensions, or liver. To determine if low extracellular [K+] might directly modulate AT1 receptor mRNA expression, primary cultures of rabbit proximal tubule cells were incubated for 1, 3, 6 or 24 h in media with or without 5 mmol/l K+. Incubation of cells in 0 mmol/l K+ caused a 99.2 +/- 32.9% increase in AT1 receptor mRNA expression at 3 h (p < 0.001; n = 14), returning to control levels by 24 h. Incubation of proximal tubule cells in 0 mmol/l K+ also caused a significant increase in basolateral membrane specific binding of [125I]-angiotensin II (p < 0.05; n = 4). These results indicate that dietary K+ deficiency and low extracellular [K+] stimulate expression of kidney AT1 angiotensin II receptors. Increased AT1 receptor mRNA and protein expression in proximal tubule may promote enhanced sodium reabsorption in K+ deficiency.
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PMID:Potassium depletion stimulates mRNA expression of proximal tubule AT1 angiotensin II receptors. 945 7

Angiotensin IV, [[des-Asp1,Arg2]ANG II or ANG-(3-8)], has been shown to preferentially bind to a novel angiotensin binding site (AT4 receptor). The cellular location and function of this receptor in the rat kidney is unknown. Autoradiography localized AT4 receptors to the cell body and apical membrane of convoluted and straight proximal tubules in the cortex and outer stripe of the outer medulla. ANG IV (0.1 pM-1 microM) elicited a concentration-dependent decrease in transcellular Na+ transport (as measured by proximal tubule O2 consumption rates) in fresh suspensions of control or nystatin-stimulated (bypasses rate-limiting step of apical Na+ entry) rat proximal tubules. The inhibitory effect of 1 pM ANG IV was unaltered by either 1 microM losartan (AT1-receptor antagonist) or 1 microM PD-123319 (AT2-receptor antagonist) and yet was abolished by 1 microM divalinal-ANG IV (AT4-receptor antagonist) or ouabain pretreatment. These results demonstrate that the kidney AT4-receptor system is localized to the proximal tubule and suggests that one potential biological role of this system is in the regulation of Na+ transport by inhibiting a ouabain-sensitive component of Na(+)-K(+)-adenosinetriphosphatase activity in the rat.
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PMID:Angiotensin IV AT4-receptor system in the rat kidney. 948 24

1. An investigation was undertaken to explore the subtype of receptor involved in mediating the actions of angiotensin II on intracellular sodium content in suspensions of isolated proximal tubules of the rat. 2. Intracellular sodium content of the proximal tubules was measured with 23Na n.m.r. spectroscopy and under these conditions basal sodium content of the tubular cells was 69.04+/-1.73 nmol mg(-1) dry weight and the ATP levels, at 8.3+/-0.9 nmol ATP mg(-1) protein, were consistent with active respiration by the tissue. 3. In the presence of 10(-4) M PD123319, a selective non-peptide AT2 receptor antagonist, intracellular sodium levels rose from steady state by 30% (P < 0.01; n = 7) within 10 min of exposure to angiotensin II 10(-11) M. Over the subsequent 30 min steady state levels were re-established. Administration of angiotensin II 10(-11) M, in the presence of the selective AT1 receptor antagonist, losartan at either 10(-6) M (n = 5) or 10(-4) M (n = 6), was without effect on intracellular sodium levels, which were significantly different (P < 0.001) from those observed when PD 123319 was present. 4. Angiotensin II 10(-5) M, administered to the tubular suspension in the presence of 10(-4) M PD123319, decreased (P < 0.01, n = 6) intracellular sodium content by 16% in the first 5 min, but in the following 25 min returned to steady state levels. However, in the presence of losartan 10(-4) M, angiotensin II 10(-5) M had no effect on intracellular sodium content which was markedly different (P < 0.001) from that obtained in the presence of PD123319. 5. These findings show that at both the high and low concentrations of angiotensin II, its modulation of intracellular sodium levels within the proximal tubule cells is mediated via the activation of AT1 receptors. The intracellular mechanism underlying this effect remain to be investigated.
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PMID:The receptor subtype mediating the action of angiotensin II on intracellular sodium in rat proximal tubules. 963 Mar 41

We examined the signal transduction cascade of angiotensin II in isolated rat proximal tubules. Angiotensin II induced a rapid (15 sec) concentration-dependent rise in intracellular free Ca2+ (EC50 = 1.7 nM). The rise in Ca2+ was blocked by the angiotensin II receptor AT1 specific antagonist SK&F 108566. This indicates that the rise in Ca2+ is fully mediated by AT1 receptors. To characterize further the antagonism by SK&F 108566, the Schild analysis was performed (pA2 = 10.9 +/- 0.14 and slope = 0.94 +/- 0.11; n=3). It indicated that SK&F 108566 is a high affinity competitive antagonist at AT1 receptors in the proximal tubule. Angiotensin II signaling also induced a rapid (5 min) rise in cGMP formation. This response was blocked by SK&F 108566, by inhibition of nitric oxide synthase, or by inhibition of soluble guanylyl cyclase. This indicates that the formation of cGMP elicited by angiotensin II is mediated by AT1 receptors and activation of the NO-cGMP pathway. Since cGMP can inhibit Na, K-ATPase activity, activation of the NO-cGMP pathway may act as a negative feedback component of angiotensin II signaling in renal proximal tubules.
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PMID:Angiotensin II signaling activities the NO-cGMP pathway in rat proximal tubules. 969 43

Angiotensin II is a key element in regulating the volume of extracellular liquid. It acts indirectly through aldosterone secretion by adrenals and directly on the renal tubule too: It regulates luminal Na+/H+ antiporters (NHE3 and possibly NHE2) after binding to membrane AT1 receptors located both on the basolateral and on the apical side of the cells. The main site of Ang II action is proximal tubule, mainly the S1 segment which has a high level of AT1 receptors. Circulating Ang II concentrations (10(-12) to 10(-10) M), increased NaCl, water and NaHCO3 reabsorption via NHE3 in the proximal tubule. There is also a synthesis of Ang II within the cells of proximal tubule, which is secreted within the lumen where the physiological concentration is stable 10(-8) M, i.e. 100 to 1000 times higher than the circulating concentration. Luminal ANG II originating from kidney has a physiological autocrine function on NaCl, water and probably NaHCO3 reabsorption, since inhibiting Ang II synthesis, by conversion enzyme inhibition, or effect, by AT1 receptor antagonists, induces a reduction of proximal tubule reabsorption. The stimulatory effects of circulating and intrarenal Ang II seem to be explained by protein kinase C stimulation and possibly by a reduction of cAMP production or by a stimulation of a non-receptor tyrosine kinase. When pharmacological doses of Ang II (> 10(-8) M) are applied in the peritubular or the luminal medium of isolated microperfused proximal tubule in vitro, a paradoxical inhibition of NHE3 was observed. These effects appear to involve arachidonic acid metabolites through the cytochrome P450 pathway and possibly a rise in cytosolic free Ca++. The physiological significance of these supraphysiological effects are unknown.
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PMID:[Effect of angiotensin ii on Na+/H+ exchangers of the renal tubule]. 985 78

Previous studies have documented that the vasoactive agonist angiotensin II (AngII) directly affects proximal tubular sodium-bicarbonate reabsorption in a biphasic manner, whereby picomolar concentrations promote reabsorption and nanomolar concentrations have the converse effect. Although it is generally agreed that the AT1 receptor subtype mediates AngII-induced sodium-bicarbonate reabsorption primarily through adenylate cyclase, the receptor subtype mediating natriuresis is less well defined. Using mouse proximal tubular cells, this study documents AT1-dependent enhancement (candesartan-inhibitable) of bicarbonate reabsorption and AT2-induced (PD123319- and CGP42112A-inhibitable) decrement of bicarbonate absorption. The signaling mechanisms were examined in rabbit proximal tubule cells in culture. The AT2 signaling involves G protein beta- and gamma-mediated phospholipase A2 activation, arachidonic acid release, and downstream events linked to Shc/Grb2/Sos and p21ras rather than protein kinase C as reported previously for AngII receptors. These observations provide a novel mechanism for AngII-AT2 receptor-mediated transport modulation.
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PMID:Renal proximal tubular AT2 receptor: signaling and transport. 989 43

The renal proximal tubule (PT) is a major site for a complete tissue renin-angiotensin system (RAS) and produces endogenous angiotensin II (ANG II). The present studies demonstrate autocrine RAS feedback in a line of origin-defective SV40 plasmid transformed immortalized rat PT cells (IRPTC) designated as line 93-p-2-1, which are highly differentiated and express all RAS components. Receptor competition assays and Southern blot following RT-PCR demonstrated that these IRPTC express AT1 and AT2 angiotensin receptor subtypes. Autocrine RAS feedback was examined following exposure to ANG II (10(-8) M), and it was noted that angiotensinogen mRNA increases significantly by 1 h and remains elevated through 24 h. The AT1 blocker losartan prevents this increase. Moreover, ANG II upregulates expression of ANG II receptor mRNA (both AT1 and AT2). Thus the present studies demonstrate positive ANG II feedback with angiotensinogen and ANG II receptors in PTC, suggesting that the main site of such intrarenal feedback in vivo is within PT. ANG II secreted by line 93-p-2-1 is increased by isoproterenol, suggesting beta-adrenergic regulation in IRPTC.
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PMID:Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine ANG II feedback. 995 Sep 52

Angiotensin II has a well described dose-dependent biphasic action on proximal tubule fluid uptake, although the concentration and effect of endogenous luminal angiotensin II remain controversial. Shrinking split-droplet micropuncture was used to examine the fluid uptake in response to the luminal application of three AT1 antagonists (losartan, EXP3174, candesartan). Addition of losartan at 10(-8) M decreased fluid uptake rate (Jva) by 17.5+/-2.2% (P<0.05). Luminal addition of EXP3174 at concentrations between 10(-9)-10(-5) M caused a dose-dependent decrease in fluid uptake, with a maximum decrease of 41.0+/-9.5% (P<0.01) at 10(-6) M. Candesartan also decreased fluid uptake, by 21.9+/-4.9% (P<0.05) at 10(-8) M and 23.6+/-5.5% (P<0.05) at 10(-5) M. All three antagonists at a low concentration (10(-8) M) decreased fluid uptake. EXP3174 and candesartan at a higher concentration (10(-5) M) also decreased fluid uptake in contrast to the previously reported effect of losartan. We conclude that the endogenous concentration of antiotensin II in the proximal luminal fluid is low and exerts a stimulatory effect on fluid absorption. Losartan at concentrations greater than 10(-6) M may have a non-selective action on fluid uptake.
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PMID:Effects of angiotensin II receptor blockade on proximal fluid uptake in the rat kidney. 1018 81


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