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)

Angiotensin II (Ang II) induces hypertrophy of cultured proximal tubular epithelial cells including the LLC-PK1 cell line. We have previously shown that this hypertrophy appears in the G1-phase of the cell cycle. Since progression through the cell cycle is controlled by a series of cyclin and cyclin-dependent kinase (CdK) complexes that may be inactivated by CdK inhibitors, we studied the expression of the CdK-inhibitor p27Kip1 in LLC-PK1 cells challenged with Ang II. Compared to cells grown in serum-free medium, Ang II treatment enhanced p27Kip1 protein, but not mRNA expression. This p27Kip1 induction was mediated through AT1-receptors. Exogenous TGF-beta also stimulated p27Kip1 protein expression. Immunoprecipitation experiments revealed that p27Kip1 preferentially associated with CdK4 in Ang II-treated LLC-PK1 cells and that the activity of this kinase was inhibited after Ang II-treatment, an effect that may be generated by increased p27Kip1 binding to cyclin D1-CdK4 complexes. In contrast, p27Kip1 was not associated with cyclin E-CdK2 complexes in Ang II-stimulated cells. Treatment of LLC-PK1 cells with p27Kip1 antisense, but not missense, oligonucleotides abolished the Ang II-mediated cell hypertrophy as measured by de novo protein synthesis and total protein content, and facilitated entry into the S-phase of the cell cycle. Our findings suggest that Ang II stimulates p27Kip1 expression in renal cells. Furthermore, this induction of the CdK-inhibitor appears pivotal in the hypertrophy induced by Ang II and elucidates the molecular mechanisms associated with this growth response in proximal tubular cells.
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PMID:Angiotensin II-stimulated hypertrophy of LLC-PK1 cells depends on the induction of the cyclin-dependent kinase inhibitor p27Kip1. 894 98

Angiotensin II may be an important mediator of neointima formation in vascular disease. This study was designed to examine the mechanisms involved in angiotensin II-stimulated migration of human and rat aortic vascular smooth muscle cells (VSMCs). VSMCs were seeded in one corner of Nunc four-well culture chambers; angiotensin II within filter paper was glued onto the wall of the opposite side. After 48 hours of incubation in serum-free medium containing growth-arresting factor, migrated cells were counted using a light microscope. Angiotensin II (2 x 10(-11) to 2 x 10(-8) mol/L) increased migration of VSMCs in a concentration-dependent manner. Interestingly, at higher concentrations of angiotensin II (up to 2 x 10(-6) mol/L), migration was reduced to levels comparable with control levels. Losartan, an AT1 receptor antagonist, prevented migration, while PD123319, an AT2 receptor antagonist, had no significant inhibitory effect. Transforming growth factor-beta 1 (TGF-beta 1; 0.01 to 10.0 pg/mL) inhibited migration induced by angiotensin II (2 x 10(-8) mol/L) in a concentration-dependent manner. A neutralizing TGF-beta antibody unmasked migratory effects of high concentrations of angiotensin II. Furthermore, angiotensin II (10(-6) mol/L) upregulated TGF-beta 1 mRNA levels fivefold in rat and fourfold in human VSMCs; this effect was prevented by losartan but not by PD123319. Thus, the effects of angiotensin II on migration of VSMCs are bimodal, ie, both migratory and antimigratory pathways are activated. Autocrine release of TGF-beta 1 induced by angiotensin II exerts an antimigratory effect in rat and human VSMCs. The AT1 receptor is involved in regulation of both pathways.
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PMID:Bimodal effects of angiotensin II on migration of human and rat smooth muscle cells. Direct stimulation and indirect inhibition via transforming growth factor-beta 1. 926 Dec 54

Angiotensin II (Ang II) is implicated in fibrosis but the precise mechanism of this effect remains unclear. In a model of chronic cyclosporine (CsA) nephropathy, we previously showed that TGF-beta1 plays a role in CsA-induced tubulointerstitial fibrosis and arteriolopathy by stimulating extracellular matrix (ECM) protein synthesis and inhibiting ECM degradation through increasing the synthesis of plasminogen activator inhibitor (PAI)-1. We hypothesized that Ang II contributes to fibrosis by inducing TGF-beta1. Salt-depleted rats were given placebo, CsA alone, CsA + nilvadipine, CsA + hydralazine/hydrochlorthiazide, CsA + losartan (AT1 receptor antagonist) or CsA + enalapril (Ang converting enzyme inhibitor) and were sacrificed at 7 and 28 days. All treated groups achieved similar blood pressures and glomerular filtration rates. The lesion of chronic CsA nephropathy was ameliorated by concomitant therapy with losartan or enalapril at 28 days, a phenomenon not observed in the other treatment groups. Similarly, Ang II blockade resulted in decreased expression of TGF-beta1 and PAI-1 by Northern and ELISA. Similarly, the expression of ECM proteins directly influenced by TGF-beta decreased with Ang II blockade. These results suggest that CsA-induced fibrosis in this model is independent of renal hemodynamics and is mediated, at least partly, through Ang II induction of TGF-beta1 expression.
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PMID:Angiotensin II blockade decreases TGF-beta1 and matrix proteins in cyclosporine nephropathy. 929 Nov 85

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

For heart, kidneys, lungs and liver alike, fibrosis represents a common pathway to their failure. Understanding pathophysiologic mechanisms involved in organ fibrosis are therefore of considerable interest, particularly given the potential for protective pharmacological strategies. Tissue repair involves inflammatory cells, including members of the monocyte/macrophage lineage, integral to initiating the repair process; and myofibroblasts, phenotypically transformed interstitial fibroblasts, responsible for collagen turnover and fibrous tissue formation. Each of these cellular events in the microenvironment of repair are associated with molecular events that lead to the de novo generation of angiotensin II (ANG II). In an autocrine/paracrine manner, this peptide regulates expression of TGF-beta 1 via angiotensin (AT1) receptor-ligand binding. It is this cytokine that contributes to phenotypic conversion of fibroblasts to myofibroblasts (myoFb) and regulates myofibroblast turnover of collagen. Angiotensin-converting enzyme (ACE) inhibition or AT1 receptor antagonism each prevent many of these molecular and cellular responses that eventuate in fibrosis and therefore have been found to be protective interventions.
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PMID:Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. 931 15

The renin-angiotensin system seems to play an important role in the pathogenesis of renal interstitial fibrosis. However, the potential direct effects of angiotensin II (Ang II) on cultured renal fibroblasts have been little studied. We have observed that rat renal interstitial fibroblasts (NRK 49F cell line) possess AT1 receptors coupled to intracellular calcium mobilization. Exposure of these cells to Ang II induced several short and long growth-related metabolic events mediated by the AT1 receptor, including c-fos gene expression, changes in cell cycle and cell proliferation. Activation of interstitial fibroblasts by Ang II could also contribute to extracellular matrix accumulation. Stimulation with Ang II increased mRNA expression of TGF-beta 1, fibronectin and type I collagen. In fact, Ang II enhanced fibronectin production via AT1 receptors by a process depending on autocrine TGF-beta secretion. The mechanism of some Ang II actions (calcium mobilization and fibronectin production) depended on protein kinase C and tyrosine kinase activation. We further investigated whether renal fibroblasts could express some components of the renin-angiotensin system. These cells constitutively expressed the angiotensinogen gene that was up-regulated by Ang II. Collectively, these results indicate that in renal interstitial fibroblasts Ang II causes hyperplasia and extracellular matrix production via the AT1 receptor. Ang II may initiate a positive feedback regulation of fibroblasts growth, inducing the expression of TGF-beta 1 and angiotensinogen genes. Ang II, acting directly on interstitial fibroblasts, may be implicated in the pathogenesis of renal fibrosis.
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PMID:Angiotensin II modulates cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblasts. 940 95

The interaction of ANG II with platelet-derived growth factor (PDGF)-BB-induced DNA synthesis was studied in cultured rat aortic smooth muscle cells. PDGF-BB-induced DNA synthesis was delayed (approximately 6-8 h) by ANG II as shown by a time-course experiment. Losartan, an AT1-receptor antagonist, blocked the transient inhibitory effect of ANG II, whereas the AT2-receptor antagonist PD-123319 had no effect. Autocrine- or paracrine-acting transforming growth factor-beta 1 (TGF-beta 1), believed to be a mediator of ANG II-induced inhibitory effects, was not responsible for the delay of PDGF-BB-induced DNA synthesis, because a potent TGF-beta 1 neutralizing antibody could not reverse this effect of ANG II, nor was the delay of the PDGF-BB effect caused by inhibition of PDGF-beta-receptor phosphorylation as shown by Western blot analysis of immunoprecipitated PDGF-beta receptor. In conclusion, our results show that ANG II can exert a transient inhibitory effect on PDGF-BB-induced proliferation via the AT1 receptor.
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PMID:PDGF-BB-induced DNA synthesis is delayed by angiotensin II in vascular smooth muscle cells. 961 86

Myofibroblasts and their potential to generate angiotensin (Ang) II and transforming growth factor beta 1 (TGF-beta 1) at sites of infarction in the rat heart have been implicated in tissue repair. These cells likewise contribute to repair in a subcutaneous pouch model of fibrous tissue formation. Their appearance in pouch tissue coincides with high density ACE and Ang II receptor binding, suggesting a role for Ang II in tissue repair. Using pouch tissue studied at different time points of repair, the present study examined the expression of requisite mRNA for Ang peptide generation: angiotensinogen, Ao; an aspartyl protease, either cathepsin-D, Cat-D, or renin: and angiotensin converting enzyme, ACE, TGF-beta 1 and type I collagen mRNA expression was also addressed. Unlike pouch studied on day 2 and 4, at 7, 14 and 21 days, we found: (a) expression of Ao, Cat-D but not renin, ACE and TGF-beta 1 mRNA; (b) Ang I and Ang II peptides in pouch tissue and exudate; (c) the presence of Cat-D activity but no renin activity; (d) an increase in type I collagen mRNA with time; (e) upregulation of pouch tissue ACE mRNA expression by lisinopril treatment, whereas AT1 and AT2 receptor antagonists (losartan and PD 123177, respectively) downregulated the expression of mRNA for ACE, when compared to untreated controls; (f) downregulation of TGF-beta 1 mRNA expression by lisinopril and losartan compared to untreated controls; and (g) PD 123177 had no effect, whereas lisinopril and losartan treatment significantly (P < 0.05) reduced type I collagen mRNA expression. Thus, in this model of fibrous tissue formation, we found expression of component genes involved in Ang peptide (I and II) and TGF-beta 1 generation and Ang II upregulation of TGF-beta 1 expression, suggesting Ang II and/or TGF-beta 1 may upregulate type I collagen expression during tissue repair. Pharmacologic intervention studies with lisinopril or losartan indicate Ang II plays a role in the reciprocal regulation of ACE mRNA expression, which modulates Ang II levels at sites of repair.
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PMID:Pouch tissue and angiotensin peptide generation. 971 Aug 8

An activated renin-angiotensin system is a major risk factor for cardiovascular events. Angiotensin II acts on AT1 and AT2 receptors. Stimulation of AT1 receptors is associated with endothelial dysfunction, mainly as the consequence of an increased vascular production of superoxide radicals, vasoconstriction, platelet activation, enhanced release of plasminogen activator inhibitor-1, activation of immediate early genes c-fos and c-jun, myocyte hypertrophy, connective tissue formation, endothelin-1 synthesis, and activation of growth factors like PDGF and TGF-beta 1. Stimulation of AT2 receptors can mitigate or abolish the growth promoting effects of AT1 receptor stimulation. The contribution of these effects--single or in combination--on the progression of atherosclerotic lesions, the phenomenon of restenosis and the process of remodeling in heart failure is being progressively elucidated. With increasing knowledge about these relationships the inhibition of AT1 receptors appears as a main target in preventive and reparative strategies in cardiovascular diseases.
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PMID:Angiotensin II and coronary artery disease, congestive heart failure, and sudden cardiac death. 983 71

Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom. We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, and VEGF expression. The expression of TGF-beta and deposition of extracellular matrix proteins follows, which is accompanied by fibrinoid vasculitis in small vessels of the heart and kidneys. Angiotensin-converting enzyme inhibitors and AT1 receptor blockers each lowered blood pressure and shifted pressure natriuresis partially leftward by different mechanisms. When combined, they normalized blood pressure, pressure natriuresis, and protected from vasculopathy completely. Renin inhibition lowered blood pressure partially, but protected from vasculopathy completely. Endothelin receptor blockade had no influence on blood pressure but protected from vasculopathy and improved survival. We show evidence that Ang II stimulates oxidative stress directly or indirectly via endothelin 1 and that NFkappaB is upregulated in this model. We speculate that the transcription factors NFkappaB and AP-1 are involved with initiating chemokine and cytokine expression, leading to the above cascade. The unique model and our pharmacological probes will enable us to test these hypotheses.
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PMID:Hypertension-induced end-organ damage : A new transgenic approach to an old problem. 993 Nov 7


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