Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pre-eclampsia, a pregnancy complication characterized by hypertension and proteinuria, is still a major cause of neonatal and maternal mortality, and acute and long-term morbidities for both mother and neonate. There is mounting evidence that an imbalance between angiogenic factors, such as VEGF (vascular endothelial growth factor) or PlGF (placental growth factor), and factors inhibiting angiogenesis, such as sFlt1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin), are closely related to the pathogenesis of pre-eclampsia. In the present issue of Clinical Science, Bills and co-workers report that VEGF(165)b, an alternative splice variant of the VEGF pre-mRNA, is up-regulated in women with normal pregnancy and that this increase was delayed or diminished in women who developed pre-eclampsia. Thus this protein could serve (alone or in combination with other parameters) as a new marker for risk assessment in terms of pre-eclampsia.
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PMID:Angiogenic factors and pre-eclampsia: an early marker is needed. 1882 76

Imatinib is a selective tyrosine kinase inhibitor that can block activity of the platelet-derived growth factor receptor (PDGFR) and that has immunomodulatory effects on various cell types. Here we measured the protective effects of imatinib in Wistar-Kyoto rats with nephrotoxic serum nephritis, a kidney disease model where CD8+ T cells and macrophages play pathogenetic roles. Groups of animals were given imatinib from one day before up to 13 days following induction of nephritis and from day 7 to 20 following disease induction. Compared to control rats, at each time point imatinib treatment caused significantly less proteinuria, lowered serum blood urea nitrogen and creatinine, and decreased the number of glomeruli with necrosis, crescents, and fibrin deposits. Imatinib-treated rats had a significant reduction in glomerular macrophage accumulation and reduced renal cortical PDGFR-beta and M-CSF receptor mRNA expression. Using colocalization we found that glomerular macrophages had reduced IL-1beta and MCP-1 protein expression. Late imatinib treatment significantly reduced proteinuria, serum blood urea nitrogen, and creatinine, and reversed renal histopathological changes. We show that imatinib has renoprotective and therapeutic properties and provide pre-clinical work that will need to be confirmed in patients with crescentic glomerulonephritis.
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PMID:Preventive and therapeutic effects of imatinib in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis. 1924 5

The number of VEGFR tyrosine kinase inhibitors (TKIs) used as an anti-cancer agent is rapidly increasing, but several issues in clinical practice remain to be elucidated. VEGFR TKIs are multikinase inhibitors that have additional targets such platelet-derived growth factor receptors, which may result in an increased efficacy as well as an increased toxicity. Efficacy in several cancers has been shown, but acquired resistance also occurs during treatment with this new class of drugs. Tumor response evaluation can be a challenge, because VEGFR TKIs can cause extensive tumor necrosis without a marked decrease in tumor size. Therefore, new response criteria and functional imaging techniques are required. In this review we will also focus on the specific toxicities and their management: hypertension, proteinuria, cardiac toxicity, fatigue, hypothyroidism, voice changes, gastrointestinal toxicity, cutaneous reactions, wound healing, hemorrhage and thromboembolic events, hematological toxicity and cerebral toxicity. Furthermore we will discuss some issues regarding the pharmacology and dosing of these drugs. This review may provide important information to clinicians who prescribe VEGFR TKIs to their patients.
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PMID:Tyrosine kinase inhibitors of VEGF receptors: clinical issues and remaining questions. 1927 99

Lung cancer is the leading cause of cancer-related death worldwide. Despite several chemotherapeutic agents, a survival plateau has been reached, so new treatment strategies are clearly needed. A strong interest is now focused on the use of targeted therapies for the management of non-small-cell lung cancer. Monoclonal antibodies against the epidermal growth factor receptor (EGFR; cetuximab) or vascular endothelial growth factor receptor (VEGFR; bevacizumab) and EGFR tyrosine kinase inhibitors (gefitinib, erlotinib) are generally well tolerated and do not have the severe systemic side effects usually seen with cytotoxic drugs. A considerable number of treated patients develop dermatologic side effects, such as acneiform eruption, xerosis, and eczema, and unfortunately, this is often one cause of negative impact on a patient's quality of life. No controlled clinical trials have been performed to manage rash, so it is necessary to provide suggestions for managing this frequent side effect. The main problems related to the class of angiogenesis inhibitors affecting VEGFRs are the exclusion of patients with brain metastases and/or squamous histology, and vascular adverse effects, such as hypertension, proteinuria, thrombosis, and hemorrhage. There are other new agents in clinical development, such as sorafenib, sunitinib, vorinostat, vandetanib, everolimus, panobinostat, and ASA404. They are all associated with a spectrum of toxicities, often reversible with interruption of dosing. Further research is required to clarify the role of targeted therapies and toxicities management.
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PMID:Toxicity of targeted therapy in non-small-cell lung cancer management. 1928 69

Renal dysfunction is a major cause of morbidity and mortality in patients with hypertension. In an attempt to understand the molecular mechanisms leading to renal dysfunction and in particular that of epidermal growth factor receptor (EGFR) and RasGTPase signaling, we analyzed global gene expression changes in the kidneys of deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats with and without treatment with AG1478, a selective inhibitor of EGFR tyrosine kinase, or FPTIII, a farnesyl transferase inhibitor known to inhibit RasGTPase. Microarray-based global gene expression analysis was performed in triplicate for each rat kidney taken from normotensive Wistar rats, DOCA-salt hypertensive (DH) rats, DH rats treated with AG1478, or DH rats treated with FPTIII. From the initial data set of 10,163 gene spots per group, upregulation of 2398 genes and downregulation of only 50 genes by more than 2-fold was observed in hypertensive rat kidneys compared to non-diseased controls. Interestingly, treatment of animals with AG1478 or FPTIII prevented upregulation of more than 97% of genes associated with hypertension in the rat kidney. Analysis of proteinuria, renal artery responsiveness and histopathology studies confirmed that DOCA-salt hypertensive rats had developed kidney damage over the study period and that this kidney dysfunction could be significantly prevented upon AG1478 or FPTIII treatment without normalising blood pressure. Taken together, our data imply that signaling cascades involving EGFR and/or RasGTPase pathways are key contributors to the induction of renal damage in hypertension and these and potentially other downstream effector molecules may serve as novel targets for therapeutic intervention.
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PMID:Global upregulation of gene expression associated with renal dysfunction in DOCA-salt-induced hypertensive rats occurs via signaling cascades involving epidermal growth factor receptor: a microarray analysis. 1941 Jun 58

The purpose of this study is to assess the changes in the expression of angiogenesis-related genes in the cellular component of the blood from preeclamptic patients. Blood samples were obtained from the preeclampsia (PE) and control participants. Cellular RNA was analyzed by reverse transcription polymerase chain reaction (PCR) to identify any angiogenesis-related genes and thereby assess the mRNA expression among women with PE and controls during weeks 35 to 41 of gestation. Significant differences were observed between PE and controls in all of the angiogenesis-related genes examined. In PE, for the increased expression of transforming growth factor-beta1 (TGF-beta1), endoglin and fms-like tyrosine kinase-1 (Flt-1); and the reduced expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF). fms-Like tyrosine kinase-1 and endoglin significantly correlated with the systolic pressure, while VEGF, Flt-1, and endoglin all correlated with proteinuria. An altered expression of angiogenesis-related genes was demonstrated in the cellular component of blood from preeclamptic patients. These findings indicate that this approach may offer an alternative way for evaluating the pathogenesis of PE.
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PMID:Expression of angiogenesis-related genes in the cellular component of the blood of preeclamptic women. 1947 89

During the last decade we have assisted in the development of new therapeutic strategies for the treatment of ovarian cancer, based on the best knowledge of molecular biology. One of the most promising strategies under investigation is antiangiogenic therapy. Bevacizumab is a monoclonal humanised antibody targeting vascular endothelial growth factor (VEGF), which has shown antitumour activity in ovarian cancer in preclinical models as well as in clinical trials, both in monotherapy and in combination with other therapies. Currently, ongoing phase III trials are testing bevacizumab as a front-line therapy with carboplatin and paclitaxel. Bevacizumab has been generally well tolerated with mild frequent toxicities (proteinuria, hypertension and bleeding). However, the drug may result in other uncommon, but potentially life-threatening side effects, such as arterial thromboembolism, wound healing complications, and gastrointestinal perforation or fistulae, which should be considered when the drug is administered. Other new therapeutic antiangiogenic strategies that include small-molecule tyrosine kinase inhibitors, antibodies neutralising the VEGF receptor (VEGFR) and soluble VEGFR hybrids (VEGF Trap) are being investigated with promising early results.
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PMID:Current status of anti-angiogenic agents in the treatment of ovarian carcinoma. 1977 93

The first aim of our study was to develop a pregnant mouse model for preeclampsia using adenoviral vector containing mouse full-length soluble fms-like tyrosine kinase 1 (sFlt-1) but not truncated sFlt-1. The second aim was to evaluate effects of recombinant mouse (rm) vascular endothelial growth factor (VEGF) and rm placental growth factor (PlGF) on a preeclampsia model induced by adenoviral vector containing mouse full-length sFlt-1. We injected adenoviral vector containing mouse full-length sFlt-1 on day 8.5 or 9.5 of gestation into pregnant Institute of Cancer Research mice, resulting in hypertension, proteinuria, and similar glomerular histological changes as those seen in human preeclamptic women with glomerular endotheliosis on day 16.5 or 17.5 of gestation. The preeclampsia models were treated with 100 microg/kg of rmVEGF164 (n=5), 100 microg/kg of rmPlGF-2 (n=5), or vehicle (n=7) twice a day for 2 days IP. The rmVEGF164 treatment significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (85+/-4 versus 97+/-2 mm Hg; P=0.018). The rmPlGF-2 treatment also significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (86+/-3 versus 97+/-2 mm Hg; P=0.018). However, proteinuria was not affected by either rmVEGF164 or rmPlGF-2. In conclusion, we, for the first time, created a mouse preeclampsia model using mouse full-length sFlt-1. VEGF and PlGF may be promising for ameliorating hypertension in women with preeclampsia. Additional study of PlGF as a potential drug for preeclampsia is warranted.
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PMID:Effect of recombinant placental growth factor 2 on hypertension induced by full-length mouse soluble fms-like tyrosine kinase 1 adenoviral vector in pregnant mice. 1978 49

Preeclampsia is the major cause of maternal and fetal mortality/morbidity. Because hypertension is an important risk factor for preeclampsia, we investigated whether hypertensive mice that overexpress human renin and angiotensinogen develop superimposed preeclampsia. Given that the mechanisms underlying this disease are still poorly understood, animal models are of great use for elucidation. Blood pressure and proteinuria were measured by telemetry and ELISA, respectively. Heart function was evaluated by echocardiography, whereas pathological cardiac hypertrophy-related genes were assessed by real-time PCR. Soluble fms-like tyrosine kinase 1 plasma concentrations were quantitated by ELISA and placental expression by real-time PCR. Transgenic mice develop de novo proteinuria during gestation and marked blood pressure elevation, which are hallmarks of superimposed preeclampsia on chronic hypertension. Abnormal placentation present in these mothers produced a significant decrease in pup and placental weight and was associated with an increased placental expression of soluble fms-like tyrosine kinase 1. We also found heightened circulating levels of this receptor, when adjusted for placental mass, as has been observed in women who suffer from preeclampsia. Cardiac hypertrophy could be observed in the transgenic mice and was exacerbated by gestation. As a result, heart function was significantly decreased, and markers of pathological hypertrophy were increased. Our data, thus, confirm the characterization of a new model of superimposed preeclampsia on chronic hypertension. Because chronically hypertensive women are at risk of developing the pathology, our model reflects a clinical reality and is, thus, an excellent tool to elucidate the molecular mechanisms triggering this disease.
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PMID:Mice overexpressing both human angiotensinogen and human renin as a model of superimposed preeclampsia on chronic hypertension. 1982

Preeclampsia (PE) is a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, which resolves on placental delivery. It is thought to be the consequence of impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries. In PE the maternal plasma concentration of free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) is decreased whereas the concentration of soluble fms-like tyrosine kinase-1 (sFlt-1) and of soluble endoglin (sEng) is increased. These soluble receptors may bind VEGF, PLGF and TGFbeta1 and TGFbeta3 in the maternal circulation, causing endothelial dysfunction in many maternal tissues. Hence there is a view that the pathogenesis is more or less clarified. According to the vascular theory, poor placentation leads to poor uteroplacental perfusion and hypoxia, which stimulates sFlt-1 and sEng production causing the maternal syndrome. This assumption has been recently challenged. The role of hypoxia as the main stimulus for release of sFlt-1 has been questioned and the role of inflammatory mechanisms has been emphasized. According to this inflammatory theory, poor placentation may predispose more to placental oxidative stress than hypoxia and endothelial dysfunction may be part of a broader disorder of systemic inflammation. Finally, the recent demonstration of activating auto-antibodies to the angiotensin 1 receptor that experimentally play a major pathogenic role in PE further suggests a pleiotropism of aetiologies for this condition. The purpose of this review is to critically evaluate the recent hypotheses and their possible insights on early diagnosis, prevention and treatment.
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PMID:Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia--a step forward but not the definitive answer. 1985 25


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