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Query: UMLS:C0004135 (ATM)
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Glomerular mesangial cells and cardiac fibroblasts have been called "myofibroblasts" because of their phenotypic characteristics (resembling both the fibroblast and muscle cells). Thus, it is not surprising that AII would have similar effects on both cell types, which play critical roles in target organ stress response and wound healing, ultimately leading to remodeling changes. These effects are primarily mediated by the AT1 receptor and include: 1) growth: hyperplasia in cardiac fibroblasts and hypertrophy in normal adult mesangial cells and 2) matrix production: there appears to be an early upregulation of fibronectin message which is later followed by an increase in collagens. It is likely that elevated production of fibronectin may activate signal transduction pathways which lead to increased expression of collagen genes, and which may be critical for the organization and laying down of collagens. Thus, an overall theme that emerges is the impact of AII on both growth and wound repair. Other potential important cellular effects of AII in these systems include: 1) stimulation of growth factors, cytokines, and arachidonic acid products that could have autocrine or paracrine effects, 2) regulation of cell migration and adhesion, 3) alteration of responses to neurohormones, 4) development and maintenance of a differentiated phenotype, and others. Molecular techniques including subtraction hybridization, differential display, antisense knockout, and development of transgenic and embryonic stem cell models will be important in defining the specific role of AII in cardiovascular and renal disease.
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PMID:Angiotensin II in cell growth and matrix production. 748 24

During the past decade, experimental and clinical evidence has indicated an important role for the renin-angiotensin system in the progressive destruction of nephrons in a wide variety of chronic renal diseases. Studies have indicated that in the subtotally nephrectomized rat model of progressive glomerulosclerosis, in experimental diabetes mellitus, in the chronic phase of puromycin aminonucleoside-induced nephrotic syndrome and in Heymann's nephritis, angiotensin-converting enzyme (ACE) inhibitors dramatically preserve both nephron structure and function. Clinical studies have similarly noted that chronic administration of ACE inhibitors inhibits progression of renal failure in type I diabetes and type II diabetes as well as primary glomerulopathies, sickle cell nephropathy, systemic lupus erythematosis, chronic pyelonephritis and adult polycystic kidney disease. Current evidence suggests that the beneficial effect of ACE inhibitors is primarily due to inhibition of angiotensin II production, and there is strong suggestive evidence for increases in local intrarenal activation of the renin-angiotensin system in these conditions. In obstructive uropathy, activation of the renin-angiotensin system has also been shown to be an important aspect of the early functional changes and may be of importance in the subsequent generation of interstitial fibrosis. In the obstructed kidney, renin and angiotensinogen production increase and type I angiotensin receptors decrease. Inhibitors of angiotensin II production and angiotensin II action partially reverse the vasoconstriction and the reduced renal blood flow, and abolish the changes in expression of AT1 MRNA induced by obstruction. Studies suggest that the angiotensin-mediated increases in tubulointerstitial fibrosis may be mediated by increased production of transforming growth factor-beta.
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PMID:Angiotensin II-mediated renal injury. 756 81

Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.
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PMID:Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy. 830 Aug 85

Since angiotensin II (ANGII) AT1-receptor antagonists have been shown to possess a beneficial effect on the course of ablation nephropathy, and since the possibility that AT2-receptors are also involved could not be ruled out, the effect of the AT1 antagonist, losartan (L), on the course of ablation nephropathy was compared wit that of PD123319 (PD), an AT2 antagonist. Wistar rats underwent surgical ablation of 5/6 of their renal parenchyma (5/6NX) and for the next 8 weeks were treated with either L alone (5 mg/kg/day), or with L + PD (10 mg/kg/day) or with PD alone. The drugs were administered in drinking water and rats drinking pure water served as controls. Whereas in both groups drinking L the survival rate was 100%, it was only 60% in controls and 66.6% in PD (no significant difference). The rats drinking L have a lower blood pressure, proteinuria and glomerulosclerosis score, and higher creatinine clearance than control and PD rats, again with no difference between these two. Cardiac and kidney remnant hypertrophy was completely abolished in both L groups, whereas it was distinctly present in the other 2 groups without a difference between them. Plasma renin activity was elevated only in both L groups. In conclusion, the beneficial effect of the AT1-receptor blocker L was again confirmed. AT2 receptors are obviously not involved in the detrimental effect of ANGII on the course of ablation nephropathy.
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PMID:Lack of a beneficial effect of PD123319, an AT2-angiotensin receptor antagonist, on the course of ablation nephropathy in the rat. 895 35

Losartan potassium is the first of a new class of orally active antihypertensive drugs which antagonise the action of angiotensin (AT) II at the AT1 receptor subtype. Losartan potassium is converted by the liver to the active metabolite E-3174, which is a more potent antagonist at the AT1 receptor. E-3174 is responsible for most of the pharmacological effects of losartan potassium, and its long half-life contributes to the extended duration of action of the drug. Losartan potassium is effective as a once-daily antihypertensive agent. In mild to moderate hypertension, losartan potassium has similar efficacy to enalapril, atenolol and felodipine extended release. When losartan potassium is combined with hydrochlorothiazide there is a further reduction in blood pressure. Losartan potassium is well tolerated in mild, moderate and severe essential hypertension, with dizziness being reported as the only drug-related adverse effect. The overall rate of patient withdrawal from therapy due to adverse experiences with losartan potassium is lower (2.3%) than that of placebo (3.7%). First-dose hypotension is uncommon, perhaps due to the slower onset of action of the drug, and cough does not appear to be a significant problem. A number of areas concerning the safety and efficacy of losartan potassium remain to be clarified. In particular, long term tolerability studies are needed; cough only became apparent as an adverse effect of ACE inhibitors after 3 to 4 years of use. Postmarketing surveillance has shown that angioedema, a rare but life-threatening adverse effect of ACE inhibitors, also occurs with losartan potassium. Further data are needed on the use of losartan potassium in patients with renal impairment before accepting the recommendation that dosage adjustment is not necessary. The pharmacokinetics and pharmacodynamics of losartan potassium in patients with hepatic disease also require further investigation. Losartan potassium increases uric acid secretion and lowers plasma uric acid levels, which may be of benefit when losartan potassium is combined with a thiazide diuretic, but which may otherwise lead to uric acid stone formation and possibly to nephropathy. Simple control of blood pressure is no longer an adequate goal in the management of hypertension. Any new antihypertensive agent should also reduce cardiovascular events, prevent or cause regression of end-organ damage such as left ventricular hypertrophy, atherosclerosis and renal failure, and should not impair quality of life. Such data on losartan potassium are not currently available. Losartan potassium is likely to be used in patients who are intolerant of ACE inhibitors, but its future in the management of hypertension will depend on long term tolerability studies and data on its effects beyond simple blood pressure control.
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PMID:A risk-benefit assessment of losartan potassium in the treatment of hypertension. 901 Jun 43

Normalization of blood pressure--and use of an ACE inhibitor or AT1-receptor blocker for patients with abnormal albumin or creatinine levels--can prevent or significantly slow the rate of progression toward end-stage renal disease.
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PMID:Prevention of diabetic nephropathy. 904 Apr 25

Transforming growth factor-beta (TGF-beta) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of chronic renal disease. The present experiment investigated the chronology of TGF-beta 1 gene expression following subtotal nephrectomy (STNx) in the rat and the effect of blocking the RAS by angiotensin converting enzyme (ACE) inhibition or by angiotensin II receptor (AT1) antagonism. Rats that had undergone subtotal nephrectomy developed hypertension, proteinuria, renal impairement, glomerulosclerosis, tubulointerstitial fibrosis and mononuclear cell infiltration. These changes were associated with a 2.5-fold increase in TGF-beta 1 gene expression during a 16-week time course. In situ hybridization localized TGF-beta 1 mRNA to sclerotic glomeruli, areas of tubuloin-terstitial injury and sites of mononuclear cell infiltration. Administration of the ACE inhibitor ramipril and the AT1 receptor blocker valsartan blunted the increase in TGF-beta 1 mRNA, and attenuated the structural and functional manifestations of injury. These data suggest an interaction between the intrarenal RAS and TGF-beta in the pathogenesis of the glomerular and tubulointerstitial fibrosis that follow a major reduction in renal mass.
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PMID:Transforming growth factor beta 1 and renal injury following subtotal nephrectomy in the rat: role of the renin-angiotensin system. 915 Apr 73

The proliferation and hypertrophy of renal tubular cells are primary features in the progression of both acute and chronic renal disease often indicating a poor prognosis. Angiotensin II (ANG II), acting alone or in combination with other growth factors, has been implicated in this process. The aims of this study were to identify the importance of both ANG II and serum-derived factors upon cellular DNA synthesis and protein synthesis in renal proximal tubular cells and to identify the roles of the ANG II receptor subtypes in these processes together with the underlying intracellular signalling mechanisms involved. Primary cultures of renal proximal tubular cells were prepared from freshly isolated rat kidney cortex. Cells were cultured in either serum-replete Dulbecco's modified Eagle's/Ham's F12 or serum-deplete defined medium containing insulin, hydrocortisone, sodium selenite, transferrin, and tri-iodothyronine. Cells were incubated with ANG II (10(-10), 10(-8), 10(-6) M) for 24-120 h either alone or in combination with losartan, PD123319, or pertussis toxin. Incubation of proximal tubular cells in the presence of serum and ANG II (10(-8) M) induced a significant early (24 h) increase in DNA synthesis, together with a significant late (96 h) increase in protein content. [3H]thymidine uptake increased by 56% (p < 0.001) and total protein content by 23% (p < 0.05). In defined media, ANG II (10(-8) M) stimulated protein synthesis only. [3H]uridine uptake, [3H]leucine uptake, and total protein content increased by 25, 57, and 17% (p < 0.05), respectively. In both serum-replete and serum-deplete media, the effects upon protein synthesis of ANG II were inhibited by pertussis toxin and losartan, but not by PD123319. ANG II is clearly a potent stimulator of renal tubular cell DNA and protein synthesis-a response mediated via the AT1 receptor coupled to a pertussis toxin sensitive Gi protein.
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PMID:Selective antagonism of the AT1 receptor inhibits the effect of angiotensin II on DNA and protein synthesis of rat proximal tubular cells. 920 86

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

The hypertrophy of renal proximal tubular cells occurs as an adaptive response to a variety of stimuli and may be involved with the progression of renal disease. Angiotensin II acting alone or in combination with other growth factors has been implicated in this process. The aims of this study were to identify the role of both angiotensin II and the angiotensin receptor subtypes in DNA synthesis and protein synthesis in human renal proximal tubular cells. Primary cultures of human renal proximal tubular cells were incubated with angiotensin II (10(-10) M, 10(-8) M, 10(-6) M) for 24 to 120 hours either alone or in combination with losartan, PD123319 or 8-bromo-cAMP. Incubation of human proximal tubular cells with angiotensin II (10(-10) M, 10(-8) M) induced a significant early increase in [3H]thymidine uptake by 19% and 56% (P < 0.01), respectively, and a later increase in total protein content by 30% (P < 0.01). The effect of angiotensin II upon DNA and protein synthesis was inhibited by 8-bromo-cAMP and losartan but not by PD 123319, indicating that the responses are mediated via the AT1 receptor and dependent upon the inhibition of adenylate cyclase.
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PMID:Selective antagonism of the AT1 receptor inhibits angiotensin II stimulated DNA and protein synthesis in primary cultures of human proximal tubular cells. 929 Nov 90


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