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

Glomerulosclerosis and tubulointerstitial fibrosis are common morphological correlates of many end-stage kidneys. There is ample evidence that transforming growth factor-beta (TGF-beta) plays a major role in these alterations by directly stimulating synthesis of many extracellular matrix components and reducing collagenase production, finally leading to renal scarring. Although many factors may induce TGF-beta expression in the kidney, one very interesting aspect is the link between angiotensin II (ANG II) and TGF-beta. Originating from observations in vascular smooth muscle cells, there are now several additional studies showing that ANG II stimulates TGF-beta expression in the kidney. Although cell culture studies have convincingly demonstrated that the vasoactive peptide directly stimulates transcription as well as bioactivation of TGF-beta, the in vivo evidence is more indirect. Nevertheless, there are several pathophysiological situations including unilateral ureteral obstruction, chronic cyclosporin A nephrotoxicity, various models of hypertension, and probably diabetic nephropathy in which ANG II-mediated TGF-beta induction has been demonstrated to play an important role in the progression of the disease. The fascinating aspect of this relationship between ANG II and TGF-beta is the fact that hemodynamic changes as well as structural changes are linked together generating a unifying model of progression of chronic renal failure with ANG II as the key player. Angiotensin-converting enzyme (ACE) inhibitor and the more recently introduced AT1-receptor blocker may be potential drugs to interfere with this ANG II-mediated TGF-beta expression. Therefore, these drugs should not only be considered as antihypertensive medications, but should rather be viewed as renoprotective substances influencing renal remodeling by preventing local TGF-beta expression.
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PMID:Link between angiotensin II and TGF-beta in the kidney. 952 2

Calcium signaling mechanisms were examined in vessel segments and dispersed single smooth muscle cells (SMC) of interlobular arteries and afferent arterioles (< 50 microns diameter) from the rat kidney. These resistance vessels were isolated from rat kidneys, using an iron oxide-sieving technique with subsequent collagenase digestion. Individual cells were identified by their characteristic oval appearance and positive staining for smooth muscle-specific alpha-actin and heavy chain myosin SM-1 and SM-2. Cytosolic calcium concentration ([Ca2+]i) was measured using fura 2 ratiometric fluorescence at 340 and 380 nm wavelength with a microscope-based photometer. Angiotensin II (ANG II) and arginine vasopressin (AVP), at concentrations of 10(-10)-10(-6) M, produced dose-dependent increases in [Ca2+]i; maximum increases were 221 +/- 49 nM for ANG II and 237 +/- 49 nM for AVP. The temporal response patterns for both agonists were characterized by a square-shaped, immediate step increase in [Ca2+]i to a near maximum level that was maintained through the recording period of 150-200 s. Responses of individual dispersed SMC and short vessel segments were similar. Losartan antagonized the action of ANG II, indicating mediation by AT1 receptors on preglomerular arteriolar SMC. The V1-selective antagonist [d(CH2)5Tyr(Me)2Tyr(NH2)9]AVP completely inhibited AVP-induced [Ca2+]i changes. The importance of calcium entry in hormone-induced changes in [Ca2+]i was demonstrated by the finding that neither ANG II nor AVP elicited a [Ca2+]i response in media rendered nominally calcium free by addition of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. Calcium entry occurred primarily through L-type, voltage-gated calcium channels as the dihydropyridine, nifedipine, completely prevented or reversed [Ca2+]i changes normally elicited by either hormone. Our results provide new information about the similarity of calcium signaling in single SMC and short segments freshly isolated from renal interlobular arteries and afferent arterioles. The observations indicate that AT1 and V1 receptors are coupled to signal transduction pathways leading to rapid changes in [Ca2+]i. Calcium mobilization appears to play a minor to nonexistent role under the experimental conditions. The predominant mechanism involves calcium entry through dihydropyridine-sensitive, voltage-gated calcium channels in single SMC from these resistance vessels.
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PMID:ANG II and vasopressin stimulate calcium entry in dispersed smooth muscle cells of preglomerular arterioles. 953 Feb 66

Experiments were conducted to gain insight into calcium signaling mechanisms triggered by angiotensin II (AngII) stimulation in vascular smooth muscle cells (SMC) freshly isolated from preglomerular vessels of normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Cytosolic calcium concentration ([Ca2+]i) was measured using ratiometric Fura-2 fluorescence and a microscope-based photometer. Vascular SMC from preglomerular vessels were isolated and dispersed using an iron oxide-sieving method combined with collagenase treatment. AngII produced rapid increases in [Ca2+]i that remained elevated for the duration of continued stimulation. The same pattern of time response was observed in WKY and in SHR. AngII elicited dose-dependent increases in [Ca2+]i in groups of individual preglomerular arteriolar SMC from both strains. AngII (10(-10) M) induced an increase from baseline levels in WKY and SHR (37+/-9 and 32+/-13 nM; P < 0.05). In response to 10(-6) M AngII, steady-state responses were 165+/-30 and 170+/-35 nM (P < 0.01). The responses did not differ between strains (P > 0.4). The effects of AngII were inhibited by 88% by the AT1 receptor blocker candesartan in renal SMC. In SMC pretreated with calcium-free medium, baseline [Ca2+]i fell by about 60 nM. Thereafter, AngII did not elicit any [Ca2+]i response either in WKY or in SHR when calcium entry was prevented. Also, after prestimulation by AngII, a calcium-free solution completely reversed the effects of AngII. This study shows that AngII acts through AT1 receptors to stimulate [Ca2+]i by a predominant action on calcium entry with no evidence for calcium mobilization. Other studies have demonstrated that calcium entry in these SMC is mediated by voltage-gated, L-type entry channels sensitive to dihydropyridine agents. No strain differences were noted between the actions of AngII on individual renal SMC from SHR and normotensive control animals.
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PMID:AT1 calcium signaling in renal vascular smooth muscle cells. 989 45

Experiments were conducted to gain insight into mechanisms responsible for exaggerated renal vascular reactivity to ANG II and vasopressin (AVP) in spontaneously hypertensive rats (SHR) during the development of hypertension. Cytosolic calcium concentration ([Ca2+]i) was measured by ratiometric fura 2 fluorescence and a microscope-based photometer. Vascular smooth muscle cells (SMC) from preglomerular arterioles were isolated and dispersed using an iron oxide-sieving method plus collagenase treatment. ANG II and AVP produced rapid and sustained increases in [Ca2+]i. ANG II elicited similar dose-dependent increases in [Ca2+]i in SMC from SHR and Wistar-Kyoto rats (WKY). In contrast, AVP caused almost twofold larger responses in afferent arteriolar SMC from SHR. ANG II effects were inhibited by the AT1 receptor antagonist losartan. AVP action was blocked by the V1 receptor antagonist [d(CH2)5,Tyr(NH2)9]AVP. In SMC pretreated with nifedipine, neither ANG II nor AVP elicited [Ca2+]i responses. Poststimulation nifedipine reversed elevated [Ca2+]i to basal levels. Short-term reductions in external [Ca2+]i (EGTA) mimicked the nifedipine effects. Our study shows that AT1 and V1 receptors stimulate [Ca2+]i by a common mechanism characterized by preferential action on voltage-gated L-type channels sensitive to dihydropyridines. Calcium signaling elicited by AT1 receptors does not differ between SHR and WKY; thus the in vivo exaggerated reactivity may be dependent on interactions with other cell types, e. g., endothelium. In contrast, AVP produced larger changes in [Ca2+]i in arteriolar SMC from SHR, and such direct effects can account for the exaggerated renal blood flow responses.
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PMID:Exaggerated Ca2+ signaling in preglomerular arteriolar smooth muscle cells of genetically hypertensive rats. 995 Sep 57

It has been shown that glomerular angiotensin II (ANG II) receptors are downregulated and protein kinase C (PKC) is activated under diabetic conditions. We, therefore, investigated ANG II receptor and PKC isoform regulation in glomerular mesangial cells (MCs) under normal and elevated glucose concentrations. MCs were isolated from collagenase-treated rat glomeruli and cultured in medium containing normal or high glucose concentrations (5.5 and 25.0 mM, respectively). Competitive binding experiments were performed using the ANG II antagonists losartan and PD-123319, and PKC analysis was conducted by Western blotting. Competitive binding studies showed that the AT1 receptor was the only ANG II receptor detected on MCs grown to either subconfluence or confluence under either glucose concentration. AT1 receptor density was significantly downregulated in cells grown to confluence in high-glucose medium. Furthermore, elevated glucose concentration enhanced the presence of all MC PKC isoforms. In addition, PKCbeta, PKCgamma and PKCepsilon were translocated only in cells cultured in elevated glucose concentrations following 1-min stimulation by ANG II, whereas PKCalpha, PKCtheta, and PKClambda were translocated by ANG II only in cells grown in normal glucose. Moreover, no changes in the translocation of PKCdelta, PKCiota, PKCzeta, and PKCmu were detected in response to ANG II stimulation under euglycemic conditions. We conclude that MCs grown in high glucose concentration show altered ANG II receptor regulation as well as PKC isoform translocation compared with cells grown in normal glucose concentration.
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PMID:Regulation of angiotensin II receptors and PKC isoforms by glucose in rat mesangial cells. 1033 51

Angiotensin II (Ang II)-induced apoptosis was demonstrated for the first time in cultured adult rat ventricular myocytes (ARVMs) isolated by retrograde heart perfusion with Krebs-Henseleit bicarbonate (KHB) buffer containing collagenase and hyaluronidase. ARVMs incubated with 10 mumol/L Ang II for 48 h showed morphological features of apoptosis (cellular shrinkage, condensation of cytoplasm) and a characteristic "ladder" of DNA bands representing integer multiples of the internucleosomal DNA length about 180-200 bp, which became more evident with further incubation up to 72 h. With shorter incubation time (< or = 24 h) or at a lower Ang II concentration (< 10 mumol/L), such changes failed to occur. This effect of Ang II could be abolished by losartan (10 mumol/L), verapamil (1 mumol/L) or staurosporine (10 nmol/L). The above results indicate that Ang II-induced apoptosis in ARVMs may be mainly mediated by Ang II type I (AT1) receptors with [Ca2+]i and protein kinase C (PKC) playing a critical role.
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PMID:Angiotensin II-induced apoptosis in cultured adult rat ventricular myocytes. 1132 51

Recently, we reported our findings regarding the elevated secretion patterns of proinflammatory cytokines obtained from peripheral blood monocytes of hypertensive patients. To investigate the direct impact of these preactivated monocytes, the adhesion of monocytes from normal controls and hypertensive patients to vascular endothelial cell monolayers was determined spontaneously and after in vitro stimulation with either lipopolysaccharide (LPS) or angiotensin II (Ang II), with or without preincubation with the AT1 receptor antagonist eprosartan. Peripheral blood monocytes from 20 patients and 20 healthy individuals were isolated by density gradient centrifugation and plastic adherence; endothelial cells were obtained from human umbilical cords by collagenase digestion. The adhesion was determined by an assay with 51Cr-radiolabeled monocytes. Oxygen species release induced by phorbol myristate acetate (PMA) as a further activation marker was analyzed for monocytes and HUVEC by chemiluminescence (CL). Spontaneous adhesion of monocytes from patients and the adhesion after stimulation with Ang II were significantly increased compared with normal controls (P<0.05). Preincubation with eprosartan diminished the adhesion in both groups to comparable levels. In monocytes, peak levels of PMA and Ang II induced CL analysis were significantly higher in patients (P<0.005). These data indicate that preactivated monocytes from hypertensives may be of pathogenic importance in atherosclerosis.
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PMID:Preactivated monocytes from hypertensive patients as a factor for atherosclerosis? 1142 15

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
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PMID:Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. 1753 8

Left ventricular dysfunction is associated with reperfusion injury occurring during open-heart surgery. There is an increased secretion of angiotensin II (Ang II) and increased matrix metalloproteinases (MMPs) activities associated with open-heart surgery that may affect the cardiac extracellular matrix (ECM). The goal of this study was to determine the effects of Ang II and selective angiotensin II receptor (AT1-R and AT2-R) blockers on the enzymatic activities of MMPs in primary adult murine cardiac fibroblasts (CF). Our hypothesis is that Aug II, with and without a selective receptor blocker, differentially affects CF MMPs activities. The CF were treated with Ang II (10(-6) M) and doses of AT1-R and AT2-R blockers (losartan and PD123319, respectively) at doses of 10(-7) to 10(-5) M for 48 hours. The Ang II-stimulated CF reduced collagenase activities by only 24% (p = 0.004); however, the MMP-2 and MMP-9 gelatinase activities were reduced by 42% and 39%, respectively (p = 0.022). The losartan dose dependently increased MMP-2 (p = 0.02) and MMP-9 (ns). PD123319 at 10(-5) M significantly reduced MMP-2 and MMP-9 activities compared with the Ang II group (p = 0.014 and p = 0.02, respectively). The doses of PD123319 at 10(-6) and 10(-7) M increased the MMP-2 and MMP-9 enzymatic activities significantly above the Ang II only group. Thus, Ang II and AT1-R and AT2-R differentially affect the collagenase and gelatinase MMPs activities released by cardiac fibroblasts.
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PMID:Effect of angiotensin II on primary cardiac fibroblast matrix metalloproteinase activities. 1763 35

Abdominal aortic aneurysm is a vascular disease which, despite the fact that it shares common risk factors with atherosclerosis, develops in parallel but as a partly independent process, through different pathogenic mechanisms. The pathogenic mechanisms involve metalloproteinase and collagenase activation, median and adventitial degradation, elastin lysis, vascular smooth cells transformation and apoptosis, collagen production and lysis imbalance combined with excessive inflammatory infiltration. Endothelial cells respond to a number of stimulating factors, including smoking, hypertension and AT1 receptor stimulation and non-uniform distribution of wall stress. Their ability to produce NO is crucial in order to adapt. Endothelial cells contribute to AAA development due to increased oxidative stress which is partly mediated by impaired NO bioavailability due to endothelial dysfunction and NADPH oxidase overexpression. In addition, they express several molecules among which adherence molecules, selectins, endothelin-1, regulating inflammatory infiltration and oxidative stress. Inflammatory cells consist of monocytes, polymorphonuclear neutrophils and lymphocytes and they are involved in the degrading process in the aortic wall by secreting proteolytic enzymes or by releasing interleukins which mediate the inflammation response. Endothelial dysfunction and arterial stiffness reflect on indices like FMD, carotid-femoral PWV and augmentation index, sometimes with controversial results. At present, surgical treatment is the only option provided in patients with large AAA, in particular. Focusing on the emerging role of endothelial cells in AAA pathology may contribute in creating new therapeutic options in a disease which has not yet a well-accepted, implemented pharmaceutical treatment.
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PMID:The Role of Endothelial Dysfunction in Aortic Aneurysms. 2630 38


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