angiotensin-i and Glioma

Glioblastoma multiforme (GBM) is the most primary brain tumor, specially characterized with the damage of blood-brain barrier (BBB). The Ang-(1-7) was proven to have an inhibitory effect on glioblastoma growth. However, its role on blood-brain barrier (BBB) and the underlying molecular mechanism remains unclear. In this study, Ang-(1-7) significantly relieved the damage of blood-brain barrier in rats with intracranial U87 gliomas as evaluated by magnetic resonance imaging (MRI). Furthermore, its treatment attenuated BBB permeability, tumor growth and edema formation. Similarly, Ang-(1-7) also decreased U87 glioma cells barrier permeability in vitro. Further analysis showed that Ang-(1-7) could effectively restore tight junction protein (claudin-5 and ZO-1) expression levels both in rats and U87 glioma cells by affecting the activation of JNK pathway. SP600125, an inhibitor of JNK, significantly enhanced the expression of Claudin-5 and ZO-1, and decreased the disruption of BBB and enhanced the efficiency of Ang-(1-7) in glioma rats. Taken together, this study demonstrated a protective role of Ang-(1-7) in glioma-induced blood-brain barrier damage by regulating tight junction protein expression. Accordingly, Ang-(1-7) may become a promising therapeutic agent against glioma.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood-Brain Barrier; Brain Edema; Brain Neoplasms; Cell Membrane Permeability; Glioma; Humans; Male; MAP Kinase Signaling System; Peptide Fragments; Rats; Rats, Sprague-Dawley; Tight Junctions; Tumor Cells, Cultured

The heptapeptide angiotensin (ANG)-(1-7) mimics some but not all the central actions of ANG II, suggesting that receptor subtypes may exist. The effects of ANG-(1-7), ANG II, and ANG I on prostaglandin (PG) E2 and prostacyclin (PGI2) synthesis were investigated in neurally derived rat C6 glioma cells. All three ANG peptides stimulated PG release in a dose-dependent manner with the order of potency ANG-(1-7) greater than ANG I greater than ANG II. PGE2 release induced by ANG-(1-7) (10(-7) M) was partially blocked by [Sar1,Ile8]ANG II (10(-6) M), [Sar1,Thr8]ANG II (10(-6) M), or the subtype 1 selective antagonist Du Pont 753 (10(-5) M) but not by the subtype 2 selective antagonist CGP 42112A (10(-7)-10(-5) M). PGI2 release was inhibited only by [Sar1,Thr8]ANG II. ANG II-induced PGE2 release was blocked by [Sar1,Thr8]ANG II (10(-6) M), [Sar1,Ile8]ANG II (10(-6) M), or Du Pont 753 (10(-7) M) but not by CGP 42112A (10(-7)-10(-5) M). In contrast, ANG II-induced PGI2 release was blocked by Du Pont 753 (10(-7) M) as well as [Sar1,Ile8]ANG II (10(-6) M) but not by [Sar1,Thr8]ANG II or CGP 42112A. Thus ANG II-stimulated PGE2 and PGI2 syntheses in C6 glioma cells are mediated via receptor subtype 1. ANG-(1-7)-induced PGE2 synthesis is also mediated via subtype 1 receptors; however, PGI2 release was blocked by [Sar1,Thr8]ANG II only.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Glioma; Imidazoles; Losartan; Oligopeptides; Peptide Fragments; Prostaglandins; Receptors, Angiotensin; Tetrazoles; Tumor Cells, Cultured

Cells of the homogeneous hybrid line neuroblastoma x glioma (NG108-15) have many neuronal properties. Immunocytochemical tests show that they contain both immunoreactive renin and angiotensin; direct radioimmunoassays show that they are positive for renin, angiotensin I, and angiotensin II; enzymatic assays show that they contain angiotensinogen and converting enzyme as well. The renin appears to be present in an enzymatically inactive form that can be activated by trypsin and then blocked by antiserum to purified mouse submaxillary renin. Renin concentration and activity are increased by enhancing cellular differentiation with dibutyryl cyclic adenosine monophosphate or by serum withdrawal. These findings demonstrate a complete renin-angiotensin system within these neuron-like cells, and suggest that activation of intracellular renin could generate angiotensin II.

Topics: Angiotensin I; Angiotensin II; Angiotensins; Animals; Cell Line; Cricetinae; Glioma; Hybrid Cells; Mice; Neuroblastoma; Peptidyl-Dipeptidase A; Radioimmunoassay; Rats; Renin