Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporine has proven to be an invaluable immunosuppressive agent in solid organ transplantation. However, its major side effect is dose-related acute and chronic nephrotoxicity. The acute effects of cyclosporine are predominantly hemodynamic and mediated by a variety of vasoactive compounds, including endothelin, thromboxane A2, and/or inhibition of nitric oxide synthase. The chronic lesion of cyclosporine nephropathy which consists of afferent arteriolopathy combined with striped tubulointerstitial fibrosis and glomerulosclerosis has been much more difficult to understand. An experimental model using the salt-depleted rat has been developed which reproduces the structural and functional changes of chronic cyclosporine nephropathy. Furthermore, it has been shown in this animal model that the renin angiotensin system within the kidney is activated and is important in the pathogenesis of this lesion. Inhibition of the renin angiotensin system with angiotensin II receptor blockade or ACE inhibition markedly reduces the tubulointerstitial fibrosis and arteriolopathy while leaving the glomerular and hemodynamic effects of the drug unchanged. Thus, in the chronic animal model, the vascular and tubulointerstitial effect of cyclosporine can be dissociated. Recent studies have shown the involvement of TGF-beta 2 and osteopontin in the scarring process. Interestingly, the TGF-beta 2 and osteopontin response can also be markedly abrogated by inhibition of the renin angiotensin system. This is of great interest since recent information has suggested that the immunosuppressive effect of cyclosporine is at least partially mediated through TGF-beta 2. The therapeutic and clinical implications of further work in this area are obvious and may lead to better management strategies for the patient who must necessarily be on long-term cyclosporine therapy.
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PMID:Insights into chronic cyclosporine nephrotoxicity. 893 36

Antisense oligonucleotide inhibition of angiotensinogen and ANG II type 1 receptor (AT(1)) mRNA translation in rat proximal tubules (PT) was examined to provide direct evidence for a role of the renin-angiotensin system (RAS) in upregulated osteopontin expression observed following mechanical cell stretch. Male Sprague-Dawley rats underwent unilateral ureteral obstruction (UUO) under Brevital anesthesia. In situ hybridization and Western blot analysis demonstrated angiotensinogen mRNA and angiotensin converting enzyme (ACE) protein localized to PTs and upregulated in obstructed kidneys, respectively, confirming an increased expression of renal RAS in vivo. In vitro studies were performed to provide mechanistic insight into ANG II-dependent osteopontin expression following mechanical cell stretch, which putatively mimics the increased PT luminal pressure post-UUO. A cationic transfection method was used to introduce either angiotensinogen or AT(1) antisense oligonucleotide into cultured rat PT cells prior to 1 h of cyclic mechanical cell stretch. Northern blot analysis revealed that PT cells subjected to cyclic mechanical stretch with/without prior transfection with a sense oligonucleotide exhibited increased osteopontin mRNA expression compared with unstretched cells. Blockade of either angiotensinogen or AT(1) mRNA translation by antisense oligonucleotide inhibition prior to cell stretch was found to significantly decrease osteopontin mRNA levels 2.4-fold (P<0.004) and 1.6-fold (P<0.001), respectively, compared with values observed in control unstretched cells. This study provides evidence that stretch-induced upregulation of osteopontin mRNA expression is mediated, in part, via production of ANG II. These results lend insight into upregulation of osteopontin via a local PT RAS leading to macrophage infiltration in the tubulointerstitium in experimental hydronephrosis.
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PMID:Angiotensinogen and AT(1) antisense inhibition of osteopontin translation in rat proximal tubular cells. 1080 82

Immunosuppressant-induced nephrotoxicity contributes to kidney graft loss in the long-term as one of the non-immunologic factors. We previously reported that correction of cyclosporine A (CsA)-induced hypomagnesemia reduced chronic CsA nephrotoxicity. This study was conducted to elucidate the mechanism of the beneficial effects of magnesium (Mg) on CsA nephrotoxicity and examine the role of the renin-angiotensin system in this mechanism. We particularly focused on CsA-induced interstitial mononuclear cell infiltration. CsA (15 mg/kg/day, s.c.) was administered daily to rats maintained on low sodium diets for 7, 14 and 28 days. The inhibitory effects of Mg supplementation and those of angiotensin converting enzyme inhibitor (ACEI) were compared for renal function, renal histology, mononuclear cell infiltration and gene expression profile. CsA lowered creatinine clearance and developed characteristic tubulointerstitial fibrosis that were mostly evident at day 28. CsA-induced impairment of renal function was ameliorated by Mg supplementation but not by ACEI. Monocyte/macrophage infiltration preceded the renal fibrosis and increased progressively with the duration of CsA administration. CsA markedly upregulated the expression of chemoattractant proteins, osteopontin and monocyte chemoattractant protein-1, concomitantly. These changes were markedly attenuated by Mg but only slightly by ACEI. CsA also promoted expression of fibrogenic molecules and extracellular matrices that were markedly attenuated by Mg but only slightly by ACEI. Similarly, CsA-induced tubulointestitial fibrosis was almost completely abolished by Mg supplementation but only partially attenuated by ACEI. These results suggested that Mg supplementation abolished CsA-induced precedent inflammatory cell influx possibly via inhibition of expression of chemoattractants and consequently suppressed tubulointerstitial fibrosis. In this beneficial mechanism, factors independent of renin-angiotensin system seem to be mainly involved.
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PMID:[Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity]. 1251 45

We investigated whether vascular smooth muscle cells (VSMC)-derived from human produce angiotensin (Ang) II upon change from the contractile phenotype to the synthetic phenotype by incubation with fibronectin (FN). Expression of alpha-smooth muscle (SM) actin, apparent in the contractile phenotype, was decreased by FN. Expressions of matrix Gla and osteopontin, apparent in the synthetic phenotype, were increased by FN. Ang II measured by radioimmunoassay (RIA) was significantly increased in human VSMC by FN. Expression of mRNAs for Ang II-generating proteases cathepsin D, cathepsin G, ACE, and chymase was increased by FN. Expressions of cathepsin D and cathepsin G proteins were also increased by FN. Ang I-generating activity, which was inhibited by an aspartyl protease inhibitor pepstatin A, was readily detected in the conditioned medium from human VSMC. Antisense oligodeoxynucleotides (ODNs) that hybridize with cathepsin D and cathepsin G significantly inhibited FN-increased Ang II in conditioned medium and cell extracts. In VSMC conditioned medium, FN-induced elevation of Ang II was significantly inhibited by temocapril but not by chymostatin. Ang II type 1 receptor antagonist CV11974 completely, and antisense cathepsin D and cathepsin G ODNs partially inhibited the FN-stimulated growth of human VSMC. These results indicate that the change of homogeneous cultures of human VSMC from the contractile to the synthetic phenotype sequentially increases expression of proteases cathepsin D, cathepsin G, and ACE, production of Ang II and productions of growth factors, culminating in VSMC proliferation. These findings implicate a new mechanism for the pathogenesis of human vascular proliferative diseases.
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PMID:Human-derived vascular smooth muscle cells produce angiotensin II by changing to the synthetic phenotype. 1281 21

Proteinuria is associated with macrophage-dependent interstitial fibrosis (IF). Osteopontin (OPN), a macrophage chemoattractant, may be involved in the transition of proteinuria to IF but protective properties have also been reported. To elucidate whether OPN may be involved in the proteinuria-induced cascade of tubulointerstitial damage, renal expression of OPN was studied during the development of proteinuria-induced renal damage and during anti-proteinuric intervention with ACE inhibition (ACEi). First, the temporal relationships between proteinuria, interstitial OPN induction, and IF in adriamycin nephrosis (AN), a model of chronic proteinuria-induced renal damage, were studied. Second, the effect of anti-proteinuric treatment on OPN expression was investigated. The time course of OPN induction and markers of renal damage was studied in rats with unilateral AN at 6-week intervals until week 30. In a second study, a renal biopsy was taken 6 weeks after induction of bilateral AN; subsequently, rats were treated with ACEi until termination (week 12). In unilateral AN, proteinuria developed gradually and stabilized at week 10. In proteinuric kidneys, OPN expression was induced from week 12 onwards. Simultaneously, a progressive increase in interstitial macrophages, alpha-smooth muscle actin (alpha-SMA), collagen type III, and focal glomerulosclerosis (FGS) was observed. In bilateral AN, ACEi reduced proteinuria and OPN protein and stabilized fibrosis. In untreated animals, OPN mRNA increased, with stable OPN protein and fibrosis and increased FGS. Thus, in AN, development of proteinuria is followed by up-regulation of OPN along with markers of renal damage. The up-regulation of OPN is reversible by anti-proteinuric treatment without a corresponding reduction in fibrosis. Whereas these data are consistent with a role for OPN in the cascade of transition from proteinuria to fibrosis, intervention with ACEi showed that reduction of OPN does not attenuate established fibrosis.
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PMID:Modulation of osteopontin in proteinuria-induced renal interstitial fibrosis. 1621 43

Peroxisome proliferator-activated receptors (PPARs) are expressed on vascular tissue. To investigate the direct vasoprotective effects of PPARgamma and PPARalpha ligands, pioglitazone (3 mg/kg/day) and bezafibrate (10 mg/kg/day) were given by gavage to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.p.) significantly increased NADPH oxidase, vascular call adhesion molecule-1 (VCAM-1), and osteopontin mRNA levels in the aorta, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Immunohistochemical analysis revealed that the expression of osteopontin protein was also enhanced in the streptozotocin-injected rat aorta. Pioglitazone or bezafibrate attenuated the streptozotocin-induced increase in the expression of NADPH oxidase and VCAM-1 mRNA. The enhanced expression of osteopontin gene and protein induced by streptozotocin was suppressed by pioglitazone, whereas treatment with bezafibrate had no effect on the expression of osteopontin. We also demonstrated that pioglitazone or bezafibrate prevented the streptozotocin-induced increase in angiotensin converting enzyme (ACE) gene and protein content, by the means of RT-PCR and Western blotting. On the other hand, the treatment of pioglitazone or bezafibrate in the present study did not affect glucose tolerance, serum insulin or lipid level in streptozotocin-induced diabetic rats. These results suggest that the direct anti-oxidant and anti-inflammatory effects of PPARs ligands in the aorta of streptozotocin-induced diabetic rats were not likely to have been mediated by the normalization of glucose or lipid metabolism, but instead these salutary effects appear to have been associated with the inhibition of the expression of ACE. In addition, pioglitazone appeared to be more effective on the suppression of osteopontin expression compared with bezafibrate.
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PMID:The direct antioxidative and anti-inflammatory effects of peroxisome proliferator-activated receptors ligands are associated with the inhibition of angiotensin converting enzyme expression in streptozotocin-induced diabetic rat aorta. 1697 61

This study was carried out to compare concentrations of osteopontin (OPN) and osteoprotegerin (OPG) in peripheral arterial disease (PAD). The study population consisted of 200 consecutive subjects in whom both OPN/OPG and ankle-brachial index were measured. It was found that OPN levels, but not OPG levels, were significantly more increased in patients with PAD than those without PAD. Serum OPN levels were significantly lower in subjects with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers than those without these agents. In this study, it has been demonstrated for the first time that serum OPN levels are related to PAD. Inhibition of renin- angiotensin system could decrease OPN levels and prevent the progression of PAD.
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PMID:Elevated osteopontin levels in patients with peripheral arterial disease. 1838 57

Aortic stenosis is the most frequent valvular heart disease. Aortic sclerosis is the first characteristic lesion of the cusps, which is considered today as the process similar to atherosclerosis. Progression of the disease is an active process leading to forming of bone matrix and heavily calcified stiff cusps by inflammatory cells and osteopontin. It is a chronic, progressive disease which can remain asymptomatic for a long time even in the presence of severe aortic stenosis. Proper physical examination remains an essential diagnostic tool in aortic stenosis. Recognition of characteristic systolic murmur draws attention and guides further diagnosis in the right direction. Doppler echocardiography is an ideal tool to confirm diagnosis. It is well known that exercise tests help in stratification risk of asymptomatic aortic stenosis. Serial measurements of brain natriuretic peptide during a follow-up period may help to identify the optimal time for surgery. Heart catheterization is mostly restricted to preoperative evaluation of coronary arteries rather than to evaluation of the valve lesion itself. Currently, there is no ideal medical treatment for slowing down the disease progression. The first results about the effect of ACE inhibitors and statins in aortic sclerosis and stenosis are encouraging, but there is still not enough evidence. Onset symptoms based on current ACC/AHA/ESC recommendations are I class indication for aortic valve replacement. Aortic valve can be replaced with a biological or prosthetic valve. There is a possibility of percutaneous aortic valve implantation and transapical operation for patients that are contraindicated for standard cardiac surgery.
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PMID:[Aortic stenosis: from diagnosis to optimal treatment]. 1872 Jul 55

Cilostazol (CILO), a selective inhibitor of phosphodiesterase 3 with potent antithrombotic property, has been shown to have a vasculoprotective effect in atherosclerosis animal models due to its potential anti-inflammatory and antioxidant actions. This study was undertaken to investigate whether CILO has in fact any vasculoprotective effects in aldosterone-induced hypertensive rats (Aldo-rats), and whether CILO affects Aldo-induced oxidative stress, nitric oxide (NO) production and pro-inflammatory gene expression. Treatment with CILO markedly ameliorated perivascular inflammatory changes in the coronary arterioles of Aldo-rats without affecting the systolic blood pressure and left ventricular weight. Treatment with CILO also prevented the increase in plasma levels of thiobarbituric acid-reactive substances, an oxidative stress marker, as well as decreased urinary NOx excretion in Aldo-rats. Furthermore, CILO almost completely inhibited a set of upregulated proinflammatory genes (ICAM-1, MCP-1, PDGF-A, osteopontin, MMP-2 and ACE), as well as NAD(P)H oxidase components (p22phox, gp91phox, p47phox) and Aldo-inducible genes (SGK-1 and NHE-1) in the aortic tissues from Aldo-rats. Taken together, this study showed for the first time that CILO prevented Aldo-induced vascular inflammation and injury without affecting the blood pressure, suggesting its vasculoprotective effect on Aldo-induced vascular injury independent of blood pressure.
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PMID:Vasculoprotective effect of cilostazol in aldosterone-induced hypertensive rats. 2001 1

Tumour markers could be helpful along the continuum of care for patients with hepatocellular carcinoma; however, there is insufficient data for routine use of most current biomarkers in clinical practice. Therefore, the backbone of early detection, diagnosis and treatment response for hepatocellular carcinoma remains imaging-based. Alpha fetoprotein is the best studied of all biomarkers and may be of benefit for early detection when used in combination with ultrasound. Several other biomarkers, including AFP-L3, DCP, osteopontin, and GP73, are also being evaluated for early detection of hepatocellular carcinoma in phase III biomarker studies. Serum and tissue-based biomarkers and genomics may aid in HCC diagnosis, prognosis, and treatment selection; however, further studies are needed to better characterize their accuracy and potential role in clinical practice.
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PMID:Hepatocellular carcinoma tumour markers: current role and expectations. 2526 Mar 12


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