Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of ovarian stimulation. Although the milder form is more common, particularly among patients undergoing gonadotropin stimulation for assisted reproductive technology, the severe form is rare. Classification schemes are clinically directed and useful in diagnosis and management of moderate and severe cases. The ovarian renin-angiotensin system, as well as vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) offers attractive theories as to the pathogenesis of this disorder. Unfortunately, clinical applications of these findings are not yet available. Possible prevention measures would include identification of patients at high risk, withholding human chorionic gonadotropin (hCG), using a gonadotropin-releasing hormone agonist to trigger ovulation, using a smaller dose of hCG, controlled gonadotropin drift, or avoidance of fresh embryo transfer by cryopreservation and frozen embryo transfer at a later date. Management of moderate to severe OHSS rests upon the principles of expanding intravascular volume and maintaining adequate urine output.
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PMID:Prevention and treatment of ovarian hyperstimulation syndrome. 898 30

The antiproteinuric effect of angiotensin-converting enzyme inhibitors underscores the importance of a hemodynamic injury and the renin-angiotensin system in the proteinuria of various glomerular diseases. Vascular endothelial growth factor (VEGF), a potent promoter of vascular permeability, is induced in mesangial cells by both mechanical stretch and TGF-beta1. This study investigates the effect of TGF-beta blockade, angiotensin II (AngII), and the interaction between AngII and stretch on human mesangial cell VEGF production. Exposure to AngII (1 microM) induced a significant increase in VEGF mRNA and protein levels (1.5+/-0.1 and 1.7+/-0.3, respectively, fold increase over control, P<0.05). The AngII receptor (AT1) antagonist Losartan (10 microM) prevented AngII-induced, but not stretch-induced, VEGF protein secretion (AngII 1.7+/-0.3, AngII + Losartan 1.0+/-0.1, P<0.05; stretch 2.4+/-0.4, stretch + Losartan 2.6+/-0.5). Stretch-induced VEGF production was also unaffected by the addition of an anti-TGF-beta neutralizing antibody (stretch 2.85+/-0.82 versus stretch + anti-TGF-beta 2.84+/-0.01, fold increase over control). Simultaneous exposure to both AngII and stretch for 12 h had an additive effect on VEGF production (AngII 1.6+/-0.1, stretch 2.6+/-0.27, AngII + stretch 3.1+/-0.35). Conversely, preexposure to stretch magnified AngII-induced VEGF protein secretion (unstretched + AngII 1.3+/-0.0, stretched + AngII 1.9+/-0.1, P<0.01) with a parallel 1.5-fold increase in AT1 receptor levels. AngII and stretch can both independently induce VEGF production; in addition, mechanical stretch upregulates the AT1 receptor, enhancing the cellular response to AngII.
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PMID:Interaction of angiotensin II and mechanical stretch on vascular endothelial growth factor production by human mesangial cells. 1020 56

Clinical and basic research has increased our knowledge of the actions of the vasoactive hormone angiotensin II (Ang II), showing that it has multifunctional properties beyond its hemodynamic effects. It is commonly accepted that Ang II is a growth factor that participates in pathological settings, including renal diseases. However, a new aspect of this peptide is coming into focus: its potential role as a proinflammatory modulator. In this review, we summarize the apparently confusing information about the properties of Ang II and discuss its relations to the inflammatory process, as well as the potential mechanisms mediated by activation of nuclear transcription factors. Ang II seems to participate in the key events of the inflammatory response: First, it increases vascular permeability (via prostaglandins and vascular endothelial cell growth factor/vascular permeability factor) thus initiating the inflammatory process. Second, it participates in the recruitment of infiltrating cells into the tissues through direct activation of the inflammatory cells or by regulation of the expression of adhesion molecules and chemokines by resident cells. Finally, Ang II may contribute to tissue repair by regulation of cell growth and matrix synthesis. The renin-angiotensin system (RAS) thus appears to serve as a vascular inflammatory regulator and may even participate in immunologically-induced inflammation. However, more often activation of the RAS has an undesirable outcome, such as overhealing, because the inflammatory repair response itself involves a functionally imperfect system.
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PMID:Angiotensin II: a double-edged sword in inflammation. 1113 26

The results of the EUCLID highlighted the importance of the renin-angiotensin system in the pathogenesis of diabetic retinopathy. We aimed to evaluate the effectiveness of candesartan cilexetil(TCV-116), a potent angiotensin II receptor antagonist, in ameliorating retinal disorders in stroke-prone spontaneously hypertensive rats(SHRSP) with storeptozotocin(STZ)-induced diabetes. Retinal VEGF mRNA expression was significantly higher and the latencies of oscillatory potentials were significantly elongated in STZ-treated SHRSP compared with a non-treated SHRSP group matched for age. Treatment with TCV-116(3 mg/kg) significantly diminished retinal VEGF mRNA expression and the latencies of oscillatory potentials, but had no effect on plasma glucose concentrations. These results suggest that TCV-116 is effective in preventing the development of diabetic retinopathy already in the early stages.
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PMID:[Ameliorative effects on retinal disorder in diabetic SHRSP (stroke-prone spontaneously hypertensive rat)]. 1239 94

The aim of this study was to evaluate the role of proangiogenic growth factors in an experimental model of ischemia/reperfusion injury (I/R) in both normotensive and hypertensive rats. Renal ischemic injury was induced in transgenic rats rendered hypertensive due to renin overproduction [TGR (mREN-2)-27] and in normotensive Hannover Sprague-Dawley rats (HanSD). Animals were treated for 12 weeks with either tacrolimus (TAC, 0.1 mg/kg per day, intramuscularly [IM]) or placebo. After 12 weeks, kidneys were harvested for morphologic, immunohistochemical, and RT-PCR analysis. Both normotensive and hypertensive untreated rats developed significantly greater proteinuria and glomerulosclerosis compared with TAC-treated rats. Immunohistologically, TGR showed higher basic fibroblast growth factor (bFGF) protein expression compared with normotensive HanSD. TAC-treated rats had higher bFGF protein expression than untreated rats. Vascular endothelial growth factor (VEGF) protein expression in glomeruli was more increased in TGR after I/R than in sham-operated animals. TAC-treated TGR hosts developed higher VEGF mRNA expression compared with both untreated and sham groups; however, there were no differences between treated and untreated normotensive HanSD animals. bFGF is involved in the fibrogenesis induced by hypertension and I/R injury. The nature of the increase in proangiogeneic growth factor expression among tacrolimus-treated animals remains to be elucidated.
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PMID:Regulators of angiogenesis in renal ischemia/reperfusion injury in normotensive and hypertensive rats: effect of tacrolimus. 1580 41

Angiotensin II (Ang II), the dominant effector of the renin-angiotensin system, elicits numerous inflammatory-proliferative responses, thereby being involved in angiogenesis. T cells play an important role in angiogenesis as well by delivering vascular endothelial growth factor (VEGF) to inflammatory sites. Since we have previously shown that pigment-epithelium-derived factor (PEDF) blocks the Ang II signaling in endothelial cells, we studied here whether PEDF could inhibit the Ang-II-induced VEGF expression in MOLT-3 T and examined the potential mechanism of PEDF inhibitory effects. Ang II significantly up-regulated VEGF mRNA levels in MOLT-3 T cells, which was inhibited by PEDF or olmesartan, an Ang II type 1 receptor blocker. PEDF blocked the Ang-II-induced reactive oxygen species (ROS) generation in MOLT-3 T cells. Furthermore, H(2)O(2) was found to up-regulate VEGF mRNA levels in MOLT-3 T cells in a dose-dependent manner. These results demonstrate that PEDF could inhibit the Ang-II-induced VEGF expression in MOLT-3 T cells via suppression of ROS generation. Blockade by PEDF of VEGF expression in T cells may become a novel therapeutic target for pathological angiogenesis.
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PMID:Pigment-epithelium-derived factor (PEDF) inhibits angiotensin-II-induced vascular endothelial growth factor (VEGF) expression in MOLT-3 T cells through anti-oxidative properties. 1662 40

Ruboxistaurin is an inhibitor of the beta isoform of protein kinase C (PKC-beta) that reduces the actions of vascular endothelial growth factor (VEGF) and attenuates the progression of diabetic retinopathy. In the glomerulus VEGF is constitutively expressed where it likely has a role in maintaining endothelial cell integrity, particularly in disease states. Given its potential use in diabetic nephropathy, we sought to determine the effects of PKC-beta inhibition on VEGF and glomerular endothelial cells in experimental diabetic nephropathy. Studies were conducted in (mRen-2)27 rat, a transgenic rodent with hypertension and an enhanced renin-angiotensin system that following induction of diabetes with streptozotocin develops many of the features of diabetic nephropathy. Moreover, to mimic the clinical context, the effects of PKC-beta inhibition were examined both with and without concomitant angiotensin-converting enzyme (ACE) inhibitor therapy. Diabetic Ren-2 rats were randomized to receive either vehicle, the ACE inhibitor, perindopril (0.2 mg/l in drinking water), ruboxistaurin (10 mg.kg(-1).day(-1), admixed in chow), or their combination and studied for 12 wk. Diabetic Ren-2 rats displayed glomerular endothelial cell loss in association with overexpression of VEGF mRNA. Both cell loss and VEGF overexpression were attenuated by the administration of either perindopril or ruboxistaurin, as single agent treatments with their combination providing additional, incremental improvements, reducing these manifestations of injury down to levels seen in nondiabetic, normotensive, nontransgenic animals. Combination therapy was also associated with additional improvements in albuminuria and glomerulosclerosis.
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PMID:Effects on protein kinase C-beta inhibition on glomerular vascular endothelial growth factor expression and endothelial cells in advanced experimental diabetic nephropathy. 1752 64

We have previously shown that advanced glycation end products (AGEs)-their receptor (RAGE) interaction elicits angiogenesis through autocrine production of vascular endothelial growth factor (VEGF), thus suggesting the active involvement of the AGEs-RAGE system in proliferative diabetic retinopathy (PDR). Since the crosstalk between the AGEs-RAGE and the renin-angiotensin system has also been proposed in the pathogenesis of PDR, we investigated here whether olmesartan, an angiotensin II type 1 receptor blocker, inhibited the AGEs-elicited angiogenesis in vitro by suppressing the NF-kappaB-mediated RAGE expression. Olmesartan significantly inhibited the AGEs-induced NF-kappaB promoter activity and RAGE gene expression in cultured microvascular endothelial cells (ECs). Further, olmesartan was found to block the AGEs-induced up-regulation of VEGF mRNA levels and consequent increase in DNA synthesis in ECs. These results demonstrated for the first time that olmesartan inhibited the AGEs signaling to angiogenesis by suppressing RAGE expression in ECs. Our present study suggests that blockade of the renin-angiotensin system by olmesartan may play a protective role against PDR by attenuating the deleterious effects of AGEs via down-regulation of RAGE.
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PMID:Olmesartan blocks advanced glycation end products (AGEs)-induced angiogenesis in vitro by suppressing receptor for AGEs (RAGE) expression. 1756 Jun 13

Inhibiting the actions of VEGF is a new therapeutic paradigm in cancer management with antiangiogenic therapy also under intensive investigation in a range of nonmalignant diseases characterized by pathological angiogenesis. However, the effects of VEGF inhibition on organs that constitutively express it in adulthood, such as the kidney, are mostly unknown. Accordingly, we examined the effect of VEGF inhibition on renal structure and function under physiological conditions and in the setting of the common renal stressors: hypertension and activation of the renin-angiotensin system. When compared with normotensive Sprague-Dawley (SD) rats, glomerular VEGF mRNA was increased 2-fold in transgenic (mRen-2)27 rats that overexpress renin with spontaneously hypertensive rat (SHR) kidneys showing VEGF expression levels that were intermediate between them. Administration of either an orally active inhibitor of the type 2 VEGF receptor (VEGFR-2) tyrosine kinase or a VEGF neutralizing antibody to TGR(mRen-2)27 rats resulted in loss of glomerular endothelial cells and transformation to a malignant hypertensive phenotype with severe glomerulosclerosis. VEGFR-2 kinase inhibition treatment was well tolerated in SDs and SHRs; although even in these animals there was detectable endothelial cell loss and rise in albuminuria. Mild mesangial expansion was also noted in hypertensive SHR, but not in SD rats. These studies illustrate: (i) VEGF has a role in the maintenance of glomerular endothelial integrity under physiological circumstances, (ii) glomerular VEGF is increased in response to hypertension and activation of the renin-angiotensin system, and (iii) VEGF signaling plays a protective role in the setting of these renal stressors.
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PMID:Role of VEGF in maintaining renal structure and function under normotensive and hypertensive conditions. 1772 4

Mesenchymal stem cells (MSCs) transplantation has been proposed as a promising means for ischemic heart disease. Vascular endothelial growth factor (VEGF) has been demonstrated to play an important role in MSCs transplantation. Angiotensin II (AngII), the most important effector peptide of the renin-angiotensin system (RAS), is also an angiogenesis factor. However, the effects of AngII on VEGF expression in MSCs and the related signaling cascades were unknown. In this experiment, we first demonstrated that incubation of MSCs with AngII-induced a rapid increase in VEGF mRNA expression and protein synthesis. However, these effects were abolished by prior treatment with AngII type 1 (AT(1)) receptor antagonist losartan while not AngII type 2 (AT(2)) receptor antagonist PD123319. The addition of either the extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126 or Akt inhibitor LY294002 also led to a marked inhibition of the AngII-induced VEGF mRNA and protein production. Taken together, these results suggested that AngII stimulated the synthesis of VEGF in MSCs through ERK1/2 and Akt pathway via AT(1) receptor.
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PMID:Angiotensin II induces vascular endothelial growth factor synthesis in mesenchymal stem cells. 1897 54


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