Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous work identified an important role for hyperglycemia in diabetic nephropathy (The Diabetes Control and Complications Trial Research Group. N Engl J Med 329: 977-986, 1993; UK Prospective Diabetes Study Group. Lancet 352: 837-853, 1998), and increased glomerular GLUT1 has been implicated. However, the roles of GLUT1 and intracellular glucose have not been determined. Here, we developed transgenic GLUT1-overexpressing mice (GT1S) to characterize the roles of GLUT1 and intracellular glucose in the development of glomerular disease without diabetes. GLUT1 was overexpressed in glomerular mesangial cells (MC) of C57BL6 mice, a line relatively resistant to diabetic nephropathy. Blood pressure, blood glucose, glomerular morphometry, matrix proteins, cell signaling, transcription factors, and selected growth factors were examined. Kidneys of GT1S mice overexpressed GLUT1 in glomerular MCs and small vessels, rather than renal tubules. GT1S mice were neither diabetic nor hypertensive. Glomerular GLUT1, glucose uptake, mean capillary diameter, and mean glomerular volume were all increased in the GT1S mice. Moderately severe glomerulosclerosis (GS) was established by 26 wk of age in GT1S mice, with increased glomerular type IV collagen and fibronectin. Modest increases in glomerular basement membrane thickness and albuminuria were detected with podocyte foot processes largely preserved, in the absence of podocyte GLUT1 overexpression. Activation of glomerular PKC, along with increased transforming growth factor-beta1, VEGFR1, VEGFR2, and VEGF were all detected in glomeruli of GT1S mice, likely contributing to GS. The transcription factor NF-kappaB was also activated. Overexpression of glomerular GLUT1, mimicking the diabetic GLUT1 response, produced numerous features typical of diabetic glomerular disease, without diabetes or hypertension. This suggested GLUT1 may play an important role in the development of diabetic GS.
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PMID:Transgenic overexpression of GLUT1 in mouse glomeruli produces renal disease resembling diabetic glomerulosclerosis. 2037 17

Hemolytic uremic syndrome (HUS) is related to a renal thrombotic microangiopathy, inducing hypertension and acute renal failure (ARF). Its pathogenesis involves an activation/lesion of microvascular endothelial cells, mainly in the renal vasculature, secondary to bacterial toxins, drugs, or autoantibodies. An overactivation of the complement alternate pathway secondary to a heterozygote deficiency of regulatory proteins (factor H, factor I or MCP) or to an activating mutation of factor B or C3 can also result in HUS. Less frequently, renal microthrombi are due to an acquired or a constitutional deficiency in ADAMTS-13, the protease cleaving von Wilebrand factor. Hemolytic anemia with schistocytes, thrombocytopenia without evidence of disseminated intravascular coagulation, and renal failure are consistently found. In typical HUS, a prodromal diarrhea, with blood in the stools, is observed, related to pathogenic enterobacteria, most frequently E. Coli O157:H7. HUS may also occur in the post partum period, and is then related to a factor H or factor I deficiency. HUS may also occur after various treatments such as mitomycin C, gemcitabine, ciclosporin A, or tacrolimus, and as reported more recently bevacizumab, an anti VEGF antibody. Atypical HUS are not associated with diarrhea, may be sporadic or familial, and can be related to an overactivation of the complement alternate pathway. More recently, some of them have been related to a mutation of thrombomodulin, which also regulates the alternate pathway of complement. In adults, several HUS are encountered in the course of chronic nephropathies: nephroangiosclerosis, chronic glomerulonephritis, post irradiation nephropathy, scleroderma, disseminated lupus erythematosus, antiphospholipid syndrome. Overall the prognosis of HUS has improved, with a patient survival greater than 85% at 1 year. Chronic renal failure is observed as a sequella in 20 to 65% of the cases. Plasma infusions and plasma exchanges are effective in most of the cases to treat hemolysis and thrombocytopenia. Steroid therapy is debated, as well as immunosuppressive drugs, including rituximab, in autoimmune forms. A new monoclonal anti-C5 antibody is tested, and seems to be effective in atypical HUS with abnormal complement alternate pathway activation. If terminal renal failure occurs, renal transplantation can be performed but the risk of recurrence, which very low in post infectious forms of HUS, is about 70 to 80% in genetic forms of complement regulatory protein deficiency.
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PMID:[Hemolytic uremic syndrome in adults]. 2039 68

Retinal vein occlusion (RVO) is the most common retinal vascular disease after diabetic retinopathy. Owing to its multifactorial nature, however, management of this condition remains a challenge. Of the two main types of RVO, branch retinal vein occlusion (BRVO) is more prevalent than central retinal vein occlusion (CRVO). Most patients develop the disease at an elderly age, and more than half of them have associated systemic disorders (e.g. hypertension, hyperlipidemia and/or diabetes mellitus). There is no evidence to suggest routine testing for heritable thrombophilias in patients with RVO. The main cause of the visual impairment is macular edema, while neovascularization of the retina and optic disc are the most serious complications leading to vitreous hemorrhage, retinal detachment and neovascular glaucoma. Macular grid laser photocoagulation is an effective treatment for macular edema in patients with BRVO and a visual acuity of 20/40 or less. Other treatment options for reducing the edema are intravitreal steroids, anti-VEGF drugs and vitrectomy. The recently introduced intravitreal application of steroids and anti-VEGF drugs may prove to be a better approach for improving visual acuity. Finally, scatter panretinal laserphotocoagulation can effectively treat neovascularization and its secondary complications.
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PMID:Retinal vein thrombosis: pathogenesis and management. 2195 4

Antiangiogenesis therapy with bevacizumab demonstrated better response rate, progression free survival and overall survival in various kind of tumors including colon, breast, lung and renal cancer. It mainly potentiates antitumor activity of cytotoxic drugs. Problems remain in high cost of antibody and adverse events such as hypertension and bleeding. Small molecules of VEGF-TKI could not show survival benefit by many randomized controlled trials except for renal and hepatic cancer.
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PMID:[Treatment with antiangiogenic drugs]. 2053 48

Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic-pharmacodynamic (PK-PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated. A previously developed PK model was used. An indirect response PK-PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.
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PMID:A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080. 2065 29

Due to demographic change the incidence of diabetic retinopathy has risen in spite of new facilities and prevention campaigns and is still one of the leading causes of blindness in Germany. The combination of focal/grid laser photocoagulation and an intravitreal anti-VEGF (vascular endothelial growth factor) regimen is the first line approach for clinically significant macular edema with foveal involvement and is evidence-based. Vitreomacular interface abnormalities can be effectively treated by modern vitreomacular surgery. Unfortunately, no proven treatment modality can be provided for ischemic maculopathy. The management of systemic risks factors, such as hyperglycemia and arterial hypertension, remains a task of great importance despite all modifications and increase of knowledge during recent years. Innovative developments in the field of intravitreal pharmacotherapy have opened up new vistas. There are good prospects that modern ophthalmology will not be limited to preserving visual function but to allow improvements and consequently enhance health-related quality of life for diabetic patients.
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PMID:[Diabetic maculopathy. Diagnosis and treatment]. 2065 39

Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and oedema, resolves on placental delivery. Its pathogenesis is thought to be associated to a hypoxic placenta. Placental hypoxia is responsible for the maternal vascular dysfunction via the increased placental release of anti-angiogenic factors such as soluble flt1 and endoglin. These soluble receptors bind VEGF, PLGF and TGFbeta1 and 3 in the maternal circulation, causing endothelial dysfunction in many maternal tissues. Despite these recent and important new molecular findings, it is important to consider that normal pregnancy is also characterized by systemic inflammation, oxidative stress and alterations in levels of angiogenic factors and vascular reactivity. Both the placenta and maternal vasculatures are major sources of reactive oxygen and nitrogen species which can produce powerful pro-oxidants that covalently modify proteins and alter vascular function in preeclampsia. Finally, the recent demonstration of activating auto-antibodies to the Angiotensin 1 receptor that experimentally play a major pathogenic role in preeclampsia further indicates the pleiotropism of aetiologies of this condition.
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PMID:Aetiology and physiopathology of preeclampsia and related forms. 2095 61

Preeclampsia is a relatively common pregnancy-related disorder. Both maternal and fetal lives will be endangered if it proceeds unabated. Recently, the placenta-derived anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG), have attracted attention in the progression of preeclampsia. Here, we established a unique experimental model to test the role of sFLT1 in preeclampsia using a lentiviral vector-mediated placenta-specific expression system. The model mice showed hypertension and proteinuria during pregnancy, and the symptoms regressed after parturition. Intrauterine growth restriction was also observed. We further showed that pravastatin induced the VEGF-like angiogenic factor placental growth factor (PGF) and ameliorated the symptoms. We conclude that our experimental preeclamptic murine model phenocopies the human case, and the model identifies low-dose statins and PGF as candidates for preeclampsia treatment.
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PMID:Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. 2123 19

The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time. Vascular endothelial growth factor inhibitors are associated with a broad range of adverse effects, with vascular toxicity being particularly serious. This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism), their incidence and severity, the current clinical management, and implications in the advanced cancer setting. Movement of these agents into the early disease setting will alter the impact of these toxicities. Search Strategy and Selection Criteria. Information for this review was collected by searching PubMed/Medline and American Society of Clinical Oncology abstract databases. The medical subject heading terms used included toxicity, hypertension, thromboembolism, hemorrhage, intestinal perforation, risk factors, pharmacokinetics, and metabolism, combined with free text search terms including, but not limited to, VEGF inhibitor*, bevacizumab, sunitinib, and sorafenib. Articles published in English before March 2010 were included, in addition to information from case reports and pharmaceutical agent package inserts.
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PMID:Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. 2144 Dec 97

Antiangiogenesis therapy for cancer may inhibit tumor growth and metastasis when combined with chemotherapy, and has received a great deal of attention over recent years. However, accurate assessments of biological efficacy and toxicity are major hurdles for this approach. Soluble VEGF receptor-1 (sFlt-1) has been reported to have a role in the pathogenesis of preeclampsia, the hallmark of which is similar to the toxicities related to antiangiogenesis therapy. Clinical evidence and animal studies support the hypothesis that sFlt-1 may contribute to hypertension and proteinuria in patients treated with anti-VEGF agents. The intratumoral imbalance between sFlt-1 and VEGF levels correlates with the malignancy grades of tumors, survival and responsiveness to therapy. The therapeutic potential of sFlt-1 as an antiangiogenic agent has been validated by an increasing number of preclinical studies. Furthermore, antiangiogenesis therapy changes the concentration of circulating VEGF, PlGF, sFlt-1, soluble VEGFR-2 and even soluble VEGFR-3, with some of these being identified as potential biomarkers of response and toxicity. All these factors suggest that sFlt-1 may prove invaluable for driving the future development of molecular therapeutics with novel targets and mechanisms of action, and its impact on antiangiogenesis therapy in cancers needs further investigation.
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PMID:Potential role of soluble VEGFR-1 in antiangiogenesis therapy for cancer. 2150 21


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