Renin in Glioblastoma Multiforme and Its Role in Neovascularization

Ariza, Aurelio; Fernandez, Leonardo A.; Inagami, Tadashi; Kim, Jung Ho; Manuelidis, Elias E.

doi:10.1093/ajcp/90.4.437

Cited by 43 publications

(23 citation statements)

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“…Angiotensinogen mRNA is present in the brain in astrocytes, whose end-feet surround brain vessels, in neurons and in ependymal cells. Renin mRNA has been demonstrated in rat glial cells and neurons (Herman et al, 1987), and renin was also demonstrated by immunohistochemistry in glioblastoma tumors (Ariza et al, 1988). In the present experiments, we found renin in glioblastoma and cerebral parenchymal cells.…”

Section: Discussionsupporting

confidence: 82%

Regulation of Aminopeptidase A in Human Brain Tumor Vasculature: Evidence for a Role of Transforming Growth Factor-β

Juillerat‐Jeanneret

Lohm

Hamou³

et al. 2000

Laboratory Investigation

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SUMMARY:Angiotensin peptides are potent vasoconstrictors, cell growth factors, and neuromodulators in normal and pathological situations. To assess the potential role of the angiotensins in brain tumor-associated vessels, the expression of the enzymes of the angiotensin cascade were evaluated in these tumors. The production of these bioactive peptides is dependent on the activities of exopeptidases, including several aminopeptidases and carboxypeptidases, producing angiotensin (Ang) I, II, III, IV and Ang 1-7. Human cerebral parenchymal and glioblastoma cells expressed renin, and tumor vasculature, but not glioblastoma cells, expressed angiotensin-converting enzyme. High aminopeptidase A (APA) activity, but no aminopeptidase N/B activity, was observed in human brain tumor vasculature, suggesting a predominant production of Ang III. Grafting of rat glioma cells in rat brains yielded tumors with high APA and low aminopeptidase N/B activities in tumor vessels, confirming human results. Tumor growth and APA activity in tumor vessels were not affected by chronic angiotensin-converting enzyme inhibition. The brain-derived EC219 endothelial cells expressed high APA activity, which was not involved in endothelial cell proliferation, but was down-regulated by exposure of cells to transforming growth factor-␤ (TGF␤) or to TGF␤-secreting tumor cells, suggesting a role for this peptide in the control of APA activity in cerebral vasculature. Thus, APA is a potential marker of chronic dysfunction, involving loss of TGF␤ function, of the metabolic blood-brain barrier, but not of neovascularization. (Lab Invest 2000, 80:973-980).

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Section: Discussionsupporting

confidence: 82%

Regulation of Aminopeptidase A in Human Brain Tumor Vasculature: Evidence for a Role of Transforming Growth Factor-β

Juillerat‐Jeanneret

Lohm

Hamou³

et al. 2000

Laboratory Investigation

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“…However, most information has been obtained in rodents. Renin expression has been previously demonstrated by immunohistochemistry in human glioblastoma (Ariza et al, 1988) and AGT synthesis by Northern blotting in nontumoral (n ¼ 3) and tumoral (n ¼ 3) astrocytic cell lines (Milsted et al, 1990). In this small series, AGT expression was higher in normal than tumoral cells, with heterogenous expression between cells.…”

Section: Discussionmentioning

confidence: 49%

Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma

Juillerat‐Jeanneret¹,

Célérier

Bernasconi³

et al. 2004

Br J Cancer

133

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The expression and function in growth and apoptosis of the renin -angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT 2 and/or AT 1 mRNAs and proteins determined by RT -PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1 -14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.

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“…18 Activation of the intraocular RAS may lead to enhanced intraocular Ang II, which, in view of its effects on growth, may contribute to the development of PDR. 66,67 Ang II is also a potent activator of TGF-␤ secretion, through which it stimulates matrix IOVS, July 2007, Vol. 48,No.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II and Its Receptor Subtypes in the Human Retina

Senanayake

Drazba

Shadrach

et al. 2007

Invest. Ophthalmol. Vis. Sci.

211

156

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PURPOSE.To quantify and evaluate the distribution of angiotensin II (Ang II) and its receptors in the human retina. METHODS. Donor eyes were obtained within 12 hours postmortem and classified as hypertensive or normotensive and diabetic or nondiabetic, based on the donors' medical histories. Ang II in retina and vitreous was quantified by RIA. Ang II receptors were characterized and quantified by competitive membrane-binding assays. Ang II, its heptapeptide metabolite Ang-(1-7), and AT1 and AT2 receptors were localized by immunohistochemistry and confocal imaging. RESULTS. Levels of Ang II in the retina were significantly higher than in vitreous (P Ͻ 0.05). Ang II in the diabetic retina had a higher median compared with that in the nondiabetic retina. Ang II and Ang-(1-7) colocalized in retinal Müller cells. The retina had the highest levels of Ang II receptors that were significantly higher than the optic nerve, retinal pigment epithelium-choroid complex, and ciliary body-iris complex (P Ͻ 0.05). AT1 receptors were more abundant than AT2 receptors in the retina. Immunoreactivity for AT1 was detected in Müller cells and on blood vessels. AT2 receptors were localized throughout the Müller cells and nuclei of ganglion cells and neurons in the inner nuclear layer. CONCLUSIONS. In the human retina, identification of Ang II and its bioactive metabolite Ang-(1-7) in Müller cells suggests that these glial cells are able to produce and process Ang II. Ang receptors were localized in the blood vessels and neural cells. Local Ang II signaling may thus allow for autoregulation of neurovascular activity. Such an autonomous system could modulate the onset and severity of retinovascular disease. (Invest Ophthalmol Vis Sci. 2007;48:3301-3311) DOI:10.1167/iovs.06-1024 D iabetic retinopathy is one of the major complications of diabetes mellitus and the leading cause of visual loss and blindness in the adult population of the United States. It has been viewed as a disorder of the retinal vasculature 1,2 ; however, evidence from numerous reports indicate that neural function of the retina is compromised before the vascular lesions are clinically diagnosed. At the cellular level, diabetes alters the structure and function of most cell types.3-9 Many factors have been implicated in the pathogenesis of diabetic retinopathy. Clinical and experimental studies have shown that the renin-angiotensin system (RAS) plays a pivotal role in the progression of the disease, presumably through local changes in blood flow and production of vascular endothelial growth factor (VEGF 10 -22 ). Furthermore, Ang II may act as an inflammatory agent by enhancing vascular permeability through prostaglandins and VEGF 23 and contribute to the recruitment of inflammatory cells by inducing chemokines and adhesion molecules. 23,24 Although an independent RAS has not been established in the retina, many reports support the concept of a paracrine RAS in this organ. [25][26][27][28] In the classic pathway, Ang II is produced by the sequential processing of plasma...

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Renin in Glioblastoma Multiforme and Its Role in Neovascularization

Cited by 43 publications

References 0 publications

Regulation of Aminopeptidase A in Human Brain Tumor Vasculature: Evidence for a Role of Transforming Growth Factor-β

Regulation of Aminopeptidase A in Human Brain Tumor Vasculature: Evidence for a Role of Transforming Growth Factor-β

Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma

Angiotensin II and Its Receptor Subtypes in the Human Retina

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