UMLS:C0033687 - FACTA Search

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)

We seek to determine: 1) whether a long-term high salt diet induces hypertension and renal injury in Sprague-Dawley (SD) rats and 2) whether the high salt diet-induced hypertension and renal injury are associated with decreased renal VEGF expression. Twelve 10-wk-old male SD rats received a high salt diet (HS, 8%) and twelve SD rats received a normal salt diet (NS, 0.5 %) for 8 weeks. Using a tail cuff, weekly monitoring showed that blood pressure increased significantly after 6, 7, & 8 wks in HS group, compared to NS group (P<0.01). At 4 wks and 8 wks of diet, mean arterial pressure (MAP) was determined in conscious rats by continuous monitoring through a catheter placed in the carotid artery. MAP was not significantly different between HS and NS group in 4 wks, but was significantly higher in HS than NS group (140+/-5.3 vs.112+/-2.2 mmHg; P<0.01) in 8 wks. Increased proteinuria and albuminuria were associated with marked renal histological abnormalities in HS group, compared to those in NS group. Northern blot and ELISA demonstrated that 8 wks of HS diet significantly decreased renal expression of VEGF mRNA and protein, compared to NS group (P<0.01). In 8 wks, total urinary excretion of sFlt-1 was significantly higher in HS than NS group (9.28+/-1.05 vs. 2.05+/-0.55 ng/day; P<0.01) whereas the plasma levels of sFlt-1 remained stable. These results suggest that a long-term HS diet induces renal injury and hypertension, which are associated with decreased renal VEGF expression in normotensive rodent animals.
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PMID:Long-term High Salt Diet Causes Hypertension and Decreases Renal Expression of Vascular Endothelial Growth Factor in Sprague-Dawley Rats. 1912 55

Hypertension, proteinuria, thromboembolic or bleeding events are well-recognized complications occurring while targeting VEGF pathway. Wound healing dysfunctions have also been described in patients undergoing major surgery. For the first time, we report wound healing delay after central venous access following DCF-VEGF-Trap. VEGF-Trap may affect both angiogenesis and reepithelialization which are necessary to the normal repair process.
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PMID:Wound healing delay after central venous access following DCF/VEGF-trap therapy. 1922 94

Clinical evidence links the inhibition of VEGF to hypertension. However, the mechanisms by which VEGF affects the pathogenesis of hypertension remain in question. We determined 1) whether administration of VEGF receptor inhibitor SU5416 enhances dietary salt-induced hypertension in Sprague-Dawley (SD) rats, and 2) whether VEGF or SU5416 directly affects proliferation of cultured human renal proximal tubular epithelial cells (HRPTEC) and endothelial nitric oxide synthase (eNOS) expression in cultured human glomerular microvessel endothelial cells (HGMEC). Ten 10-wk-old male SD rats received a high sodium diet (HS; 8%) and the other 10 SD rats received a normal sodium diet (NS; 0.5%) for 4 wks. After 2 wks of the dietary program, five rats were administered with SU5416 at 10 mg x kg(-1) x day(-1) ip or DMSO (vehicle) for 14 days in HS and NS groups. Mean arterial pressure was significantly higher in rats treated with SU5416, as opposed to those treated with DMSO and fed with HS for 4 wk (157.6 +/- 3.9 vs. 125.9 +/- 4.3 mmHg, P < 0.01). Increased proteinuria and albuminuria were associated with marked renal histological abnormalities in HS group with SU5416 administration, compared with those in the vehicle HS group. 3H-thymidine incorporation assay showed that SU5416 blocked the actions of both exogenous and endogenous VEGF on the proliferation of HRPTEC. VEGF (10 ng/ml) significantly increased eNOS protein levels by 29% in cultured HGMEC, but its action was completely abolished by SU5416. These results suggest that VEGF receptor inhibition enhances dietary salt-induced hypertension and kidney injury, possibly by direct damage on renal cells and decreasing NO production by eNOS.
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PMID:Vascular endothelial growth factor receptor inhibitor enhances dietary salt-induced hypertension in Sprague-Dawley rats. 1942 Feb 88

Chronic renal ischemia and hypoxia in the tubulointerstitium are involved in the mechanisms of progressive chronic kidney disease. Previous studies showed that the decoction of a combination of two Chinese herbs, Astragalus membmnaceus var. mongholicus and Angelica sinensis (A & A) has antifibrotic effects through multiple pathways in different animal models. In this study, remnant kidney model was employed to investigate whether A & A affect the expression of VEGF, the density of the renal microvasculature and thus alleviate the renal injury. Rats were divided randomly into four groups: sham group (N-31), 5/6 Nx group (5/ 6 nephrectomy, N=43), A & A treated group (A & A group, N=40, A & A 12 g/kg/d po), enalapril treated group (Ena group, N=56, enalapril 4 mg/kg/d po). Rats from each group were sacrificed at the 2th, 4th, 8th and 12th weeks respectively after surgery and treatment The 24 h urinary protein excretion, serum creatinine (Scr) and urea were measured. The collagen IV (COL-IV), fibronectin (FN), aminopeptidase P (APP) and VEGF were stained using immunohistochemistry. The COL-IV, FN and APP were semi-quantitatively analyzed. Peritubular capillary density in the cortical interstitial area was quantified. The level of VEGF was assayed by ELISA. The results revealed that Scr, urea and urinary protein excretion remained constant at each time point in sham group. Compared to sham group, 5/6 Nx group was shown severe glomerulosclerosis, tubulointerstitial lesions and vascular damage, as well as higher level of Scr from the 2nd week (72.3 +/- 5.2 vs. 48.6 +/- 2.6 micromol/L P < 0.05) to the 12th week (71.9 +/- 8.0 vs. 55.7 +/- 4.5 micromol/L P < 0.05). Although there was no significant difference in Scr level after treatment of enalapril or A & A (P > 0.05), kidney damage was alleviated at the 8th and the 12th week in the two treatment groups (P < 0.05, vs. 5/6 Nx group). The urinary protein excretion of 5/6 Nx group was significantly increased from the 4th week, it was 1.5, 2.4 and 3.8 fold of that of sham group at the 4th, 8th and 12th week, respectively. Compared to 5/6 Nx group, proteinuria was decreased by enalapril to 59%, 33% at 8th and 12th week. After A & A administration, urinary protein excretion decreased to 66%, 56%, 75%, 55% of 5/6 Nx group at the 2nd, 4th, 8th and 12th, respectively (P < 0.05). Compared with sham group, there was increased expression of FN and COL-IV in rats with 5/6 Nx. After A & A or enalapril administration, the expression of FN and COL-IV was significantly decreased compared with that in the 5/6 Nx group at 8th and 12th week (P < 0.05). On the other hand, the capillary density was decreased at the 8th and 12th week in 5/6 Nx rats (P < 0.01). In A & A-treated group, similarly with enalapril group, the amount of APP-positive glomerular capillary increased by 36% (P < 0.01), and the peritubular capillary density was increased 94% at 8th week and 52% at 12th week compared with 5/6 Nx group (P < 0.05). The renal level of VEGF was decreased in 5/6 Nx rats, but increased at the 8th and 12th week in A & A group (P < 0.05, vs. 5/6 Nx group). In conclusion, A & A has renoprotective effects by suppression of extra cellular matrix deposition in 5/6 Nx rat. The renoprotective effects may be associated with reduction of proteinuria, up-regulation of VEGF which may reduce the loss of capillaries and improve microstructure dysfunction.
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PMID:A combination of Chinese herbs, Astragalus membranaceus var. mongholicus and Angelica sinensis, improved renal microvascular insufficiency in 5/6 nephrectomized rats. 1956 35

HIV-1 Nef induces podocyte proliferation and dedifferentiation by activating the Stat3 and MAPK1,2 pathways. Activation of Stat3 also occurs in human kidneys affected by HIV-associated nephropathy (HIVAN), but its contribution to the development of HIVAN is unknown. Here, we generated HIV-1 transgenic mice (Tg26) with either 75% Stat3 activity (Tg26-SA/+) or 25% Stat3 activity (Tg26-SA/-). The kidneys of Tg26-SA/+ mice, but not Tg26-SA/- mice, showed increased Stat3 phosphorylation. The Tg26-SA/+ phenotype was not different from Tg26 mice, but Tg26-SA/- mice developed significantly less proteinuria, glomerulosclerosis, and tubulointerstitial injury. Tg26-SA/+ mice exhibited reduced expression of podocyte differentiation markers and increased expression of VEGF and proliferation markers as compared to Tg26-SA/- mice. Primary podocytes isolated from Tg26-SA/+ mice showed increased Stat3 phosphorylation and reduced expression of podocyte differentiation markers. The tubulointerstitial compartment and isolated tubules of Tg26-SA/+ mice also had increased Stat3 phosphorylation and expression of Stat3 target genes. We confirmed that the expression of the HIV-1 transgene and reduction of Stat3 activity did not affect T and B cell development. In conclusion, Stat3 plays a critical role in the pathogenesis of HIVAN.
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PMID:Reduction of Stat3 activity attenuates HIV-induced kidney injury. 1972 33

Pre-eclampsia, a pregnancy-specific multi-organ syndrome characterized by widespread endothelial damage, is a new risk factor for cardiovascular disease. No therapies exist to prevent or treat this condition, even to achieve a modest improvement in pregnancy length or birth weight. Co-administration of soluble VEGFR-1 [VEGF (vascular endothelial growth factor) receptor-1; more commonly known as sFlt-1 (soluble Fms-like tyrosine kinase-1)] and sEng (soluble endoglin) to pregnant rats elicits severe pre-eclampsia-like symptoms. These two anti-angiogenic factors are increased dramatically prior to the clinical onset of pre-eclampsia and are quite possibly the 'final common pathway' responsible for the accompanying signs of hypertension and proteinuria as they can be reversed by VEGF administration in animal models. HO-1 (haem oxygenase-1), an anti-inflammatory enzyme, and its metabolite, CO (carbon monoxide), exert protective effects in several organs against oxidative stimuli. In a landmark publication, we showed that the HO-1 pathway inhibits sFlt-1 and sEng in cultured cells and human placental tissue explants. Both CO and NO (nitric oxide) promote vascular homoeostasis and vasodilatation, and activation of VEGFR-1 or VEGFR-2 induced eNOS (endothelial nitric oxide synthase) phosphorylation, NO release and HO-1 expression. Our studies established the HO-1/CO pathway as a negative regulator of cytokine-induced sFlt-1 and sEng release and eNOS as a positive regulator of VEGF-mediated vascular morphogenesis. These findings provide compelling evidence for a protective role of HO-1 in pregnancy and identify it as a target for the treatment of pre-eclampsia. Any agent that is known to up-regulate HO-1, such as statins, may have potential as a therapy. Any intervention achieving even a modest prolongation of pregnancy or amelioration of the condition could have a significant beneficial health impact worldwide.
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PMID:Can the biology of VEGF and haem oxygenases help solve pre-eclampsia? 1990 54

Angiogenesis is essential for normal tissue and even more so for solid malignancies. At present, inhibition of tumor angiogenesis is a major focus of anticancer drug development. Bevacizumab, a humanized antibody against VEGF, was the first antiangiogenic agent to be approved for advanced non-small cell lung cancer, breast cancer and colorectal cancer. The most commonly observed adverse events are hypertension, proteinuria, bleeding and thrombosis. Sunitinib, a small molecule blocking intracellular VEGF, KIT, Flt3 and PDGF receptors, which regulate angiogenesis and cell growth, is approved for the treatment of advanced renal cell cancer (RCC) and malignant gastrointestinal stromal tumor. The most frequent adverse events include hand-foot syndrome, stomatitis, diarrhea, fatigue, hypothyroidism and hypertension. Sorafenib, an oral multikinase inhibitor, is approved for the second-line treatment of advanced RCC and upfront treatment of advanced hepatocellular carcinoma. Most common adverse events with sorafenib are dermatologic (hand-foot skin reaction, rash, desquamation), fatigue, diarrhea, nausea, hypothyroidism and hypertension. More recently, cardiovascular toxicity has increasingly been recognized as a potential adverse event associated with sunitinib and sorafenib treatment. Elderly patients are at increased risk of thromboembolic events when receiving bevacizumab, and potentially for cardiac dysfunction when receiving sunitinib or sorafenib. The safety of antiangiogenic drugs is of special concern when taking these agents for longer-term adjuvant or maintenance treatment. Furthermore, newer investigational antiangiogenic drugs are briefly reviewed.
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PMID:Antiangiogenic drugs in oncology: a focus on drug safety and the elderly - a mini-review. 1994 Apr 66

Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, edema and proteinuria, resolves spontaneously on placental delivery. Its pathogenesis is thought to involve placental hypoxia, which leads to maternal vascular dysfunction through increased placental release of anti-angiogenic factors such as the soluble form of VEGF receptor-1 (VEGFR1). VEGFR1 binds VEGF and PIGF, which are also produced by villous trophoblastic cells. In the absence of VEGF and PIGF in the maternal circulation, endothelial dysfunction occurs in several vascular territories (liver, kidneys, brain, heart, lungs, etc.). In experimental models, sVEGFR1 not only has an anti-angiogenic action but also augments endothelial expression of NO synthase through intracellular transduction. When NO production is increased, pericytes and perivascular smooth muscle cells are recruited and their adhesion to endothelial cells is strongly stimulated. This can hinder both trophoblast invasion and increase uteroplacental flow during preeclampsia.
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PMID:[Defective placental implantation and its effects on maternal endothelial function]. 2012 Mar 87

Endothelial cell damage and impaired angiogenesis substantially contribute to the progression of chronic renal failure (CRF). The effect of endothelial progenitor cell (EPC) treatment on the progression of CRF is yet to be determined. We performed 5/6 nephrectomy to induce CRF in C57BL/6 mice. EPCs were isolated from bone marrow, grown in conditioned medium, and characterized with surface marker analysis. The serial changes in kidney function and histological features were scrutinized in CRF mice and EPC-treated CRF (EPC-CRF) mice. Adoptively transferred EPCs were present at the glomeruli and the tubulointerstitial area until week 8 after transfer. In CRF mice, renal function deteriorated steadily over time, whereas the EPC-CRF group showed less deterioration of renal function as well as reduced proteinuria along with a relatively preserved kidney structure. Renal expression of proinflammatory cytokines and adhesion molecules was already decreased in the EPC-CRF group at the early stage of disease, at which point the renal function and histology of CRF and EPC-CRF mice were not different. Angiogenic molecules including VEGF, KDR, and thrombospondin-1, which were decreased in the CRF group, were restored by EPC treatment. In conclusion, EPCs trafficked into the injured kidney protected the kidney from the inflammatory condition and consequently resulted in functional and structural renal preservation. Our study suggests EPCs as a potential candidate for a novel therapeutic approach in CRF.
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PMID:Bone marrow-derived endothelial progenitor cells confer renal protection in a murine chronic renal failure model. 2048 99

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

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