Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major limitation to the clinical use of cyclosporine (CsA) is renal toxicity. In the past, the lack of an animal model of chronic CsA nephropathy has hampered the study of its pathogenesis. Rats given CsA and placed on a low sodium diet (LSD) develop a histology similar to human lesions of chronic CsA nephropathy, a phenomenon not observed in animals on a normal sodium diet (NSD). We have previously shown that transforming growth factor-beta1 (TGF-beta1) is involved in the CsA-induced renal fibrosis in rats on a LSD. We hypothesized that sodium depletion is critical to the increase in TGF-beta1 expression, which, in turn, results in excessive matrix accumulation. Pair-fed rats were placed on a NSD or LSD, treated with CsA or vehicle, and killed at 7 or 28 days (N = 4 to 6 in each group). All rats achieved similar blood pressure control, and all CsA-treated rats achieved similar CsA blood levels. However, while CsA did not affect creatinine clearance in rats on a NSD, it lowered creatinine clearance in rats on a LSD (P < 0.01). Cyclosporine-induced tubulointerstitial fibrosis and arteriolopathy was observed at 28 days only in the rats on a LSD (P < 0.05). In addition, peripheral renin activity was increased only in the rats on a LSD (P < 0.01), while it remained normal in the rats on a NSD. In addition, CsA-treated rats on a LSD developed a progressive increase in the mRNA expression of TGF-beta1 and the matrix proteins biglycan and type I collagen at 7 and 28 days. Most of the changes were seen at 28 days (P < 0.001 for TGF-beta1, P < 0.01 for biglycan and type I collagen). On the other hand, CsA treatment in rats on a NSD did not affect the mRNA expression of TGF-beta1 and matrix proteins. Most of the changes in the immunofluorescence deposition of the glycoproteins tenascin and fibronectin EDA+ were in the tubulointerstitium and vessels of the kidneys of rats on a LSD and were mostly significant at 28 days, in accordance with the characteristic histology of chronic CsA nephropathy. The mRNA expression of plasminogen activator inhibitor-1, a protease inhibitor involved in matrix degradation and stimulated by TGF-beta1, was observed only in kidneys of rats on a LSD (P < 0.01). Since sodium depletion elevates peripheral renin activity, our experiments suggest a role for the renin-angiotensin system in the expression of TGF-beta1 and matrix proteins in CsA-induced renal fibrosis of rats on a LSD.
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PMID:Sodium depletion enhances fibrosis and the expression of TGF-beta1 and matrix proteins in experimental chronic cyclosporine nephropathy. 921 4

The renin-angiotensin system (RAS) has been implicated in the development of hypertensive glomerulosclerosis. However, there are no experimental findings clearly demonstrating activation of glomerular RAS in hypertensive nephropathy. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as an animal model of hypertensive glomerulosclerosis, we examined the relationship between the sequential changes in urinary albumin excretion (UAE), renal morphology, and glomerular mRNA expression for transforming growth factor-beta (TGF-beta) and fibronectin (FN) and glomerular mRNA levels for RAS components, and determined the effects of the angiotensin II (Ang II) type 1 (AT-1) receptor antagonist (candesartan) and equihypotensive hydralazine on these parameters. In SHRSP, UAE was normal at nine weeks of age and increased by 12 weeks. Plasma renin activity, plasma Ang II concentration, and angiotensin converting enzyme (ACE) activity were not higher in 9- and 12-week-old SHRSP than in WKY. RNase protection assay revealed higher glomerular mRNA levels for angiotensinogen, ACE, and AT-1a and AT-1b receptors in 9-, 12-, and 14-week-old SHRSP than in WKY. The glomerular mRNA levels for TGF-beta and FN in SHRSP were increased from nine weeks of age. SHRSP had a greater glomerulosclerosis index (GSI) at 24 weeks of age than did WKY. Administration of candesartan for two weeks, but not of hydralazine, markedly reduced UAE and normalized mRNA levels for TGF-beta, FN, and RAS components. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis in rats. We conclude that in SHRSP, RAS activation and increased sensitivity to Ang II in glomeruli play important roles in the progression of glomerulosclerosis.
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PMID:Candesartan prevents the progression of glomerulosclerosis in genetic hypertensive rats. 940 67

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 clinical use of tacrolimus (FK506) is limited by nephrotoxicity. The pathogenesis of fibrosis in chronic FK506 nephrotoxicity remains unknown. Because transforming growth factor (TGF)-beta plays a key role in the fibrogenesis of many diseases, including cyclosporine nephrotoxicity, we studied a salt-depleted rat model of chronic FK506 nephropathy in which clinically relevant FK506 blood levels are obtained and which shows similarities to the lesions described in patients receiving FK506. Pair-fed rats were treated with either FK506 (1 mg/kg/day s.c.) or an equivalent dose of vehicle and were killed at 7 or 28 days. Characteristic histologic changes of tubular injury, interstitial fibrosis, and arteriolopathy developed in FK506-treated rats at 28 days and were accompanied by worsening kidney function, decreased concentrating ability, and enzymuria. FK506-treated kidneys had a progressive increase in the expression of TGF-beta1 and matrix proteins (biglycan, tenascin, fibronectin, and type I collagen). This effect seems to be specific because the expression of type IV collagen, a basement membrane collagen, was not affected. Matrix deposition was present mostly in the tubulointerstitium and vessels in accordance with the FK506 chronic lesion. The expression of plasminogen activator inhibitor-1, a protease inhibitor influenced by TGF-beta, followed TGF-beta1 and matrix proteins, suggesting that the fibrosis of chronic FK506 nephropathy likely involves the dual action of TGF-beta1 on matrix deposition and degradation. Since both peripheral and tissue renin expression were elevated with FK506, the renin-angiotensin system may play a role in the pathogenesis of this condition.
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PMID:Mechanism of fibrosis in experimental tacrolimus nephrotoxicity. 942 27

Tsukuba hypertensive mice (THMs) are transgenic mice carrying human renin and angiotensinogen genes. The aim of this study was to evaluate the role of the renin-angiotensin system (RAS) in cardiac hypertrophy and renal disorders in THMs. After a 2-wk control period, 10-wk-old THMs were treated with lisinopril (ACEI group) or hydralazine (hydralazine group) or left untreated (control group) for 8 wk. C57BL/6 mice of similar age (wild group) were used as normal controls. Systolic blood pressure and urinary albumin excretion were measured once a week. All mice were sacrificed at 20 wk of age, and heart to body weight ratio, cardiac myocyte diameter, renal glomerular sclerosis index, and glomerular size were measured. Fibronectin expression was also evaluated. At 20 wk of age, systolic blood pressure and urinary albumin excretion in the control group were significantly higher than those in the wild group and significantly lower than those in the ACEI and hydralazine groups. Heart to body weight ratio and cardiac myocyte diameter were significantly higher in the hydralazine and control groups than in the other groups. Renal glomerular sclerosis index and glomerular size were also significantly higher in the control group than in the other groups, and there were significant differences between the ACEI and hydralazine groups in these variables. Fibronectin expression was marked in the control and hydralazine groups. These findings suggest that the RAS plays an important role in cardiac hypertrophy in THMs, but that both the RAS and elevation of blood pressure contribute to the pathogenesis of renal glomerular sclerosis.
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PMID:Role of the renin-angiotensin system in cardiac hypertrophy and renal glomerular sclerosis in transgenic hypertensive mice carrying both human renin and angiotensinogen genes. 958 7

Antiatherogenic effects of imidapril and involvement of renin angiotensin system were examined in experimental atherosclerosis induced by feeding a high-cholesterol diet to Cynomolgus monkeys. Eighteen male monkeys were divided into three groups and placed under (1) normal diet (normal group), (2) high-cholesterol diet (control group), (3) high-cholesterol diet with imidapril (20 mg/kg body wt/day, orally) treatment (imidapril group). At the end of the experiment, the normal group showed no apparent atherosclerosis in their aorta evaluated by oil red-O staining, while the control group exhibited marked atherosclerotic involvement of the intimal surface of the aorta (58.4 +/- 9.3%, P < 0.01). Imidapril reduced systolic blood pressure and atherosclerotic involvement (24.1 +/- 5.5%, P < 0.05). Total cholesterol content of the descending thoracic aorta was also significantly reduced in the imidapril group. In the atherosclerotic vessels, angiotensin converting enzyme (ACE) activity evaluated by quantitative in vitro autoradiography was significantly increased in the intimal lesion. Further evaluation revealed angiotensin II (Ang II) type I (AT1) receptor density was significantly increased in the medial lesion and type II (AT2) receptor density in the adventitia. When the progression of atherosclerosis was impeded by imidapril treatment, the ACE activity level as well as the AT1 and AT2 receptor density remained at normal. Expression of mRNA for fibronectin, TGF-beta1, types I and III collagen was studied by Northern blot analysis. No significant differences in types I and III collagen mRNA levels were found between the control and imidapril group. On the other hand, mRNA expression for fibronectin and TGF-beta1 were much lower in the imidapril group than in the control group. These results suggest that increased production of Ang II and activated receptors may be involved in atherosclerotic process in this model and also antiatherogenic effect of imidapril may be derived from reduction of local Ang II production as well as its hypotensive action.
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PMID:Induction of angiotensin converting enzyme and angiotensin II receptors in the atherosclerotic aorta of high-cholesterol fed Cynomolgus monkeys. 967 83

Angiotensin (Ang) II is considered the effector peptide of the renin-angiotensin system (RAS) that acts as a renal growth factor. Some studies have shown that the angiotensin degradation product Ang III presents some biological activities, though its role in renal pathology has not been explored. We have observed that in renal interstitial fibroblasts Ang III induces c-fos gene expression, suggesting a potential role of Ang III in the control of cell proliferation. To study the involvement of Ang III in matrix regulation, we determined whether Ang III increased TGF-beta gene expression and fibronectin production in cultured rat mesangial cells and renal interstitial fibroblasts, the main effector cells in glomerular and interstitial fibrosis, respectively. In both cell types, treatment with Ang III (10(-7) M) for six hours up-regulated gene expression of transforming growth factor-beta 1 (TGF-beta 1; 2.3- and 2.2-fold, respectively). This peptide also increased fibronectin production in renal interstitial fibroblasts. All these data suggest that Ang III could contribute to matrix accumulation. Activation of local RAS has been described during renal damage. Renal cells express angiotensinogen mRNA that was up-regulated in response to Ang II and Ang III stimulation, and therefore both peptides may participate in the generation of angiotensin peptides in the kidney. In conclusion, our results suggest that the angiotensin degradation product Ang III could participate in the pathogenesis of key events of renal diseases, supporting the hypothesis that other peptides of the RAS besides Ang II may be involved in renal injury.
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PMID:Angiotensin III up-regulates genes involved in kidney damage in mesangial cells and renal interstitial fibroblasts. 983 82

Fibrosis impairs cardiac function. This project has determined the expression and deposition of collagens and fibronectin and cardiac function in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat after inhibition of the renin-angiotensin system. DOCA-salt hypertension was induced in 8-wk-old male Wistar rats by uninephrectomy and administration of DOCA (25 mg every fourth day, subcutaneously) and 1% NaCl in the drinking water for 4 wk. Starting 2 wk after surgery, rats were given either oral captopril (100 mg/kg), oral candesartan cilexetil (2 mg/kg), or subcutaneous spironolactone (50 mg/kg) daily for 2 wk (reversal protocol). DOCA-salt rats failed to gain weight with markedly increased water intake and decreased food intake; drug treatment did not alter these parameters. Systolic BP increased from 116+/-5 mmHg in uninephrectomized rats to 179+/-7 mmHg in DOCA-salt rats and was not decreased by treatment (captopril 172+/-1 mmHg; candesartan 187+/-2 mmHg; spironolactone 178+/-3 mmHg). Captopril, candesartan, and spironolactone reversed the increased collagen I mRNA in DOCA-salt rats; only candesartan reversed the increased collagen III mRNA. Collagen IV mRNA was unchanged in DOCA-salt rats and following treatment. Total fibronectin mRNA increased without changing the proportion of fibronectin mRNA as the fetal isoforms EIIIA and EIIIB. Captopril, candesartan, and spironolactone reversed the increased deposition of perivascular and interstitial collagen in DOCA-salt rats; the increased cardiac fibronectin deposition was reversed by candesartan and spironolactone. Captopril, candesartan, and spironolactone also attenuated or reversed the increased diastolic stiffness and the increased dP/dt but not the increased rate-pressure products in DOCA-salt rat hearts. Thus, inhibition of the renin-angiotensin system reverses cardiac fibrosis in DOCA-salt rats and returns some indices of myocardial function to normal.
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PMID:Reversal of cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats by inhibition of the renin-angiotensin system. 989 55

Hypertension and kidney damage in the double transgenic rat (dTGR) harboring both human renin and human angiotensinogen genes are dependent on the human components of the renin angiotensin system. We tested the hypothesis that monocyte infiltration and increased adhesion molecule expression are involved in the pathogenesis of kidney damage in dTGR. We also evaluated the effects of long-term angiotensin-converting enzyme (ACE) inhibition, AT1 blockade, and human renin inhibition on monocyte recruitment and inflammatory response in dTGR. Systolic blood pressure and 24-hour albuminuria were markedly increased in 7-week-old dTGR as compared with age-matched normotensive Sprague Dawley rats. We found a significant monocyte/macrophage infiltration in the renal perivascular space and increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the interstitium, intima, and adventitia of the small renal vessels. alphaLbeta2 integrin and alpha4beta1 integrin, the corresponding ligands for ICAM-1 and VCAM-1, were also found on infiltrating monocytes/macrophages. The expression of plasminogen activator inhibitor-1 and fibronectin in the kidneys of dTGR were increased and distributed similarly to ICAM-1. In 4-week-old dTGR, long-term treatment with ACE inhibition (cilazapril), AT1 receptor blockade (valsartan), and human renin inhibition (RO 65-7219) (each drug 10 mg/kg by gavage once a day for 3 weeks) completely prevented the development of albuminuria. However, only cilazapril and valsartan were able to decrease blood pressure to normotensive levels. Interestingly, the drugs were all equally effective in preventing monocyte/macrophage infiltration and the overexpression of adhesion molecules, plasminogen activator inhibitor-1, and fibronectin in the kidney. Our findings indicate that angiotensin II causes monocyte recruitment and vascular inflammatory response in the kidney by blood pressure-dependent and blood pressure-independent mechanisms. ACE inhibition, AT1 receptor blockade, and human renin inhibition all prevent monocyte/macrophage infiltration and increased adhesion molecule expression in the kidneys of dTGR.
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PMID:Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. 993 Nov 35

The renin-angiotensin-aldosterone system has emerged as a potential candidate for the accumulation of collagen in cardiac fibroblasts. The traditional renin-angiotensin-aldosterone system can be considered a system in which circulating angiotensin II or aldosterone is delivered to target tissue or cells. However, an independent local renin-angiotensin system has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of angiotensin II can be mediated. These actions of angiotensin II are primarily mediated through angiotensin II receptors of the subtype I (AT1). When evaluating the effects of angiotensin II in situ, changes in circulating levels and local production both have to be taken into account. Functional angiotensin II receptors have been documented in cardiac fibroblasts although the presence of aldosterone receptors in cardiac fibroblasts is obscure, and the expression of mRNA for mineralocorticoid receptors in cardiac fibroblasts has been described. In vitro, angiotensin II increased cardiac fibroblast-mediated collagen synthesis and mRNA levels of collagen type I, type III, pro-alpha 1 (I) collagen, pro-alpha 1 (III) collagen and fibronectin, and inhibited matrix metalloproteinase I activity. The ability of angiotensin II to induce collagen synthesis and expression of collagen in cardiac fibroblasts may be mediated by an increase in transforming growth factor-beta 1 in an autocrine/paracrine fashion. The angiotensin II-stimulated secretion and expression of collagen was completely abolished by AT1 receptor antagonism, but not affected by AT2 receptor antagonism. The discordant findings that have been reported concerning the in vitro effect of aldosterone on collagen synthesis in cardiac fibroblasts can at least partly be attributed to differences in methodology such as the use of the total population or a sub-population of cardiac fibroblasts. In vivo, chronic infusion of angiotensin II or aldosterone increased the collagen volume fraction in the ventricles. Angiotensin-converting enzyme (ACE) inhibition and AT1 receptor antagonism, but not AT2 receptor antagonism, reduced collagen deposition in the myocardium in spontaneously hypertensive rats. The cardioprotective mechanism of action of ACE inhibitors can be attributed to local blockade of the formation of angiotensin II, to the degradation of bradykinin or to the release of nitric oxide and/or eicosanoids. Angiotensin-converting enzyme inhibitors also reduced collagen deposition in rat myocardium following myocardial infarction suggesting that collagen deposition may in part result from mechanisms other than through AT1 receptors. However, further research is necessary to unravel the various mechanisms involved in the action of angiotensin-converting enzyme inhibitors or of AT1 receptor antagonists on collagen deposition in the myocardium.
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PMID:Antagonism of the renin-angiotensin-aldosterone system and collagen metabolism in cardiac fibroblasts. 1038 25


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