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)

Retinopathy is the most feared complication of diabetes, compromising quality of life in most sufferers. Almost all patients with type 1 diabetes will develop retinopathy over a 15- to 20-year period, and approximately 20-30% will advance to the blinding stage of the disease[1]. Greater than 60% of patients with type 2 diabetes will have retinopathy. This situation is highlighted by the frightening statistic that diabetic retinopathy (DR) remains the most common cause of vision impairment in people of working age in Western society. With the global epidemic of type 2 diabetes, this predicament is set to worsen as over 360 million people are projected to suffer from diabetes and its complications by 2030. Vision loss from diabetes is due to a number of factors, including haemorrhage from new and poorly formed blood vessels, retinal detachment due to contraction of deposited fibrous tissue, and neovascular glaucoma resulting in an increase in intraocular pressure. Diabetic macular oedema is now the principal cause of vision loss in diabetes and involves leakage from a disrupted blood-retinal barrier. In terms of treatment, there is clear evidence that strict metabolic and blood pressure control can lower the risk of developing DR and reduce disease progression. Laser photocoagulation and vitrectomy are effective in preventing severe vision loss in DR, particularly in the most advanced stages of the disease. However, both procedures have limitations. This review examines evidence from preclinical and clinical studies that shows that targeting inhibition of the renin-angiotensin system, vascular endothelial growth factor, corticosteroids, protein kinase C, growth hormone, and advanced glycation end-products are potential treatments for DR.
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PMID:Update on the treatment of diabetic retinopathy. 1826 28

This study was performed in order to evaluate the role of angiotensin II in physiological angiogenesis. Human umbilical vein endothelial cells (HUVEC) were stained for angiotensin II type 1 receptor (AGTR1) immunocytochemically and for gene expression of renin-angiotensin system (RAS) components. The regulation of the angiogenesis-associated genes vascular endothelial growth factor (VEGF) and angiopoietins (ANGPT1 and ANGPT2) were studied using quantitative RT-PCR. Furthermore, we examined the effect of angiotensin II on the proliferation of HUVEC using Ki-67 as well as BrdU immunocytochemistry and investigated whether the administration of the AGTR1 blocker candesartan or the VEGF antagonist FLT1-Fc could suppress the observed angiotensin II-dependent proangiogenic effect. AGTR1 was expressed in HUVEC and the administration of angiotensin II significantly increased the gene expression of VEGF and decreased the gene expression of ANGPT1. Since the expression of ANGPT2 was not affected significantly the ratio of ANGPT1/ANGPT2 was decreased. In addition, a significantly increased endothelial cell proliferation was observed after stimulation with angiotensin II, which was suppressed by the simultaneous administration of candesartan or the VEGF antagonist FLT1-Fc. These results indicate the potential capacity of angiotensin II in influencing angiogenesis by the regulation of angiogenesis-associated genes via AGTR1. Since VEGF blockade opposed the effect of angiotensin II on cell proliferation, it is hypothesised that VEGF mediates the angiotensin II-dependent effect in concert with the changes in angiopoietin expression. This is the first report of the RAS on the regulation of angiogenesis-associated genes in physiology.
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PMID:Regulation of endothelial proliferation by the renin-angiotensin system in human umbilical vein endothelial cells. 1839 Jun 90

Recent reports indicated that tissue renin-angiotensin system (RAS) was upregulated and angiotensin II type 1 receptor signaling plays crucial roles in ocular inflammation and neovascularization; however, the precise mechanism for activating tissue RAS had not been defined until recently. (Pro)renin receptor, a recently identified molecule existing in the major organs but not in the circulation, has attracted growing attention as an activator of tissue RAS. When the handle region of the prorenin prosegment binds to (pro)renin receptor, prorenin undergoes a conformational change to its enzymatically active state without the conventional proteolysis of the prorenin prosegment. Systemic treatment with a peptide with the structure of the handle region (handle region peptide; HRP), which competitively binds to (pro)renin receptor as a decoy peptide and inhibit the nonproteolytic activation of prorenin, resulted in the suppression of retinal inflammation and neovascularizaion in the rodent models. Retinal expression of RAS-related inflammatory and angiogenic molecules, such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, and vascular endothelial growth factor, was also suppressed with application of HRP. These findings demonstrate that nonproteolytically activated prorenin plays a significant role in the ocular inflammation and neovascularization.
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PMID:Pathologic roles of prorenin and (pro)renin receptor in the eye. 1850 82

The renal renin-angiotensin system plays a major role in determining the rate of chronic renal disease progression. Treatment with activators of the vitamin D receptor retards the progression of experimental chronic renal disease, and vitamin D is known to suppress the renin-angiotensin system in other organs. Here we determined if the beneficial effects of paricalcitol (19-nor 1,25-dihydroxyvitamin D(2)) were associated with suppression of renin-angiotensin gene expression in the kidney. Rats with the remnant kidney model of chronic renal failure (5/6 nephrectomy) were given two different doses of paricalcitol thrice weekly for 8 weeks. Paricalcitol was found to decrease angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA levels in the remnant kidney by 30-50 percent compared to untreated animals. Similarly, the protein expression of renin, renin receptor, the angiotensin type 1 receptor, and vascular endothelial growth factor were all significantly decreased. Glomerular and tubulointerstitial damage, hypertension, proteinuria, and the deterioration of renal function resulting from renal ablation were all similarly and significantly improved with both treatment doses. These studies suggest that the beneficial effects of vitamin D receptor activators in experimental chronic renal failure are due, at least in part, to down-regulation of the renal renin-angiotensin system.
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PMID:Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. 1914 59

Hemodynamic stress in concert with metabolic pathways that are activated by hyperglycemia, glycated proteins, and oxidative stress induce a host of growth factors in the kidney. The fibrogenic cytokine transforming growth factor-beta (TGF-beta), through its Smad3 signaling pathway, is the etiologic agent of renal hypertrophy and the accumulation of mesangial extracellular matrix components in diabetes. Neutralizing anti-TGF-beta antibodies, antisense TGF-beta1 oligodeoxynucleotides or knocking off the Smad3 gene prevent and/or reverse the hypertrophic and profibrotic effects of the diabetic state in mice. However, there is limited evidence to support a role for TGF-beta in the development of albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is also increased in animal models of diabetic kidney disease, appears to act in a novel autocrine signaling mode to induce the podocytopathy of diabetes, especially the genesis of albuminuria. Future strategies for therapy of diabetic nephropathy may therefore need to involve interception of both the TGF-beta and the VEGF signaling pathways to counter the matrix accumulation and to improve the albuminuria. Interception of the renin-angiotensin system may achieve this goal but other novel strategies will need to be developed that would be more efficacious. However, a note of caution should be raised not to lower the heightened activities of these two signaling pathways much below normal levels because a basal activity for each is essential for the optimal homeostasis of glomerular cells.
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PMID:Different roles for TGF-beta and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy. 1884 17

Hypertension and osteoporosis are two major age-related disorders; however, the underlying molecular mechanism for this comorbidity is not known. The renin-angiotensin system (RAS) plays a central role in the control of blood pressure and has been an important target of antihypertensive drugs. Using a chimeric RAS model of transgenic THM (Tsukuba hypertensive mouse) expressing both the human renin and human angiotensinogen genes, we showed in this study that activation of RAS induces high turnover osteoporosis with accelerated bone resorption. Transgenic mice that express only the human renin gene were normotensive and yet exhibited a low bone mass, suggesting that osteoporosis occurs independently of the development of hypertension per se. Ex vivo cultures showed that angiotensin II (AngII) acted on osteoblasts and not directly on osteoclast precursor cells and increased osteoclastogenesis-supporting cytokines, RANKL and vascular endothelial growth factor (VEGF), thereby stimulating the formation of osteoclasts. Knockdown of AT2 receptor inhibited the AngII activity, whereas silencing of the AT1 receptor paradoxically enhanced it, suggesting a functional interaction between the two AngII receptors on the osteoblastic cell surface. Finally, treatment of THM mice with an ACE inhibitor, enalapril, improved osteoporosis and hypertension, whereas treatment with losartan, an angiotensin receptor blockers specific for AT1, resulted in exacerbation of the low bone mass phenotype. Thus, blocking the synthesis of AngII may be an effective treatment of osteoporosis and hypertension, especially for those afflicted with both conditions.
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PMID:Activation of renin-angiotensin system induces osteoporosis independently of hypertension. 1884 24

The receptor-associated prorenin system (RAPS) refers to pathogenic mechanisms whereby prorenin binding to its receptor activates both the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling pathways. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R)-mediated inflammation in choroidal neovascularization (CNV), a central abnormality of vision-threatening age-related macular degeneration, the association of receptor-associated prorenin system with CNV has not been defined. Here, (pro)renin receptor blockade in a murine model of laser-induced CNV led to the significant suppression of CNV together with macrophage infiltration and the up-regulation of intercellular adhesion molecule-1, (ICAM-1) monocyte chemotactic protein-1, (MCP-1) vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. To clarify the role of signal transduction via the (pro)renin receptor in CNV, we used mice in which renin-angiotensin system was deactivated by either the pharmacological blockade of AT1-R with losartan or the genetic ablation of AT1-R or angiotensinogen. Compared with wild-type controls, these mice exhibited significant reduction of CNV and macrophage infiltration, both of which were further suppressed by (pro)renin receptor blockade. The (pro)renin receptor and phosphorylated extracellular signal-regulated kinases (ERK) were co-localized in vascular endothelial cells and macrophages in CNV. (Pro)renin receptor blockade suppressed ERK activation and the production of MCP-1 and VEGF, but not ICAM-1, VEGFR-1, or VEGFR-2, in AT1-R-deficient mice with CNV and in losartan-treated microvascular endothelial cells and macrophages. These results indicate the significant contribution of RAPS to CNV pathogenesis.
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PMID:(Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system. 1897 4

Hepatocellular carcinoma (HCC) is a hypervascular tumor, and tumor progression and prognosis is associated with angiogenesis. Extracellular matrix remodeling and inflammation play important roles in hepatocarcinogenesis. Some ingredients of extracellular matrix such as endostatin and sulfated polysaccharide, some immunomodulatory agents and cox-2 inhibitor suppress the angiogenesis of HCC. Because vasculogenic mimicry is associated with high tumor grade, some differentiation agents are used to inhibit antiagiogenesis. Besides suppressing the proliferation directly, somatostatin inhibits angiogenesis to suppress growth indirectly. Copper chelator prevents copper from functioning as a cofactor in angiogenesis. The renin-angiotensin system is frequently activated in patients with chronic liver diseases. Perindopril, an angiotensin converting enzyme inhibitor, inhibits angiogenesis by reducing vascular endothelial growth factor (VEGF) production. Kinase inhibitors of VEGF and epidermal growth factor receptors are expected to be of benefit for some patients. Following transarterial embolisation and/or resection, antiangiogenic therapy could prevent the recurring and metastasis. Hypoxia enhances the proliferation, suppresses the differentiation and apoptosis, and induces multidrug resistance of HCC. Because antiangiogenic therapies induce hypoxia, it should be borne in mind the side affects of antiangiogenic therapy. Because long-acting antiangiogenent are needed to control cancer, it needs more clinical studies to confirm the drug resistance of antiangiogenetic therapy.
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PMID:New strategy of antiangiogenic therapy for hepatocellular carcinoma. 1899 74

Intervention in the RAAS (renin-angiotensin-aldosterone system) is one of the leading pharmacotherapeutic strategies, among others, used for the treatment of cardiovascular disease to improve the prognosis after myocardial infarction and to reduce hypertension. Recently, regenerative progenitor cell therapy has emerged as a possible alternative for pharmacotherapy in patients after myocardial infarction or ischaemic events elsewhere, e.g. in the limbs. Angiogenic cell therapy to restore the vascular bed in ischaemic tissues is currently being tested in a multitude of clinical studies. This has prompted researchers to investigate the effect of modulation of the RAAS on progenitor cells. Furthermore, the relationship between hypertension and endothelial progenitor cell function is being studied. Pharmacotherapy by means of angiotensin II type 1 receptor antagonists or angiotensin-converting enzyme inhibitors has varying effects on progenitor cell levels and function. These controversial effects may be explained by involvement of multiple mediators, e.g. angiotensin II and angiotensin-(1-7), that have differential effects on mesenchymal stem cells, haematopoietic progenitor cells and endothelial progenitor cells. Importantly, angiotensin II can either stimulate endothelial progenitor cells by improvement of vascular endothelial growth factor signalling, or invoke excessive production of reactive oxygen species causing premature senescence of these cells. On the other hand, angiotensin-(1-7) stimulates haematopoietic cells and possibly also endothelial progenitor cells. Furthermore, aldosterone, bradykinin and Ac-SDKP (N-acetyl-Ser-Asp-Lys-Pro) may also affect progenitor cell populations. Alternatively, the variability in effects of angiotensin II type 1 receptor and angiotensin-converting enzyme inhibition on cardiovascular progenitor cells might reflect differences between the various models or diseases with respect to circulating and local tissue RAAS activation. In the present review we discuss what is currently known with respect to the role of the RAAS in the regulation of cardiovascular progenitor cells.
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PMID:The role of the renin-angiotensin-aldosterone system in cardiovascular progenitor cell function. 1913 71

To assess the beneficial effects of the angiotensin II type 1 receptor blocker telmisartan on a non-obese animal model of reduced function and mass of islet beta-cells prior to the development of diabetes, Spontaneously Diabetic Torii (SDT) rats were treated with telmisartan at 8 weeks of age. At 24 weeks of age, the treatment with telmisartan dose-dependently ameliorated hyperglycemia and hypoinsulinemia, and high-dose (5 mg/kg/day) treated SDT rats did not developed diabetes. Real-time RT-PCR analysis revealed that treatment with high-dose telmisartan reduced mRNA expression of local renin-angiotensin system (RAS) components, components of NAD(P)H oxidase, transforming growth factor-beta1 and vascular endothelial growth factor in the pancreas of male SDT rats. Immunohistochemical and Western blot analyses revealed that treatment with telmisartan also reduced expression of p47(phox). These results suggest that treatment with telmisartan reduces oxidative stress by local RAS activation and protects against islet beta-cell damage and dysfunction. These findings provide at least a partial explanation for the reduced incidence of new-onset diabetes that has been observed in several clinical trials involving angiotensin II type 1 receptor blockers and ACE inhibitors.
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PMID:Telmisartan, an angiotensin II type 1 receptor blocker, prevents the development of diabetes in male Spontaneously Diabetic Torii rats. 1917 Nov 32


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