Le système rénine-angiotensine dans le cerveau humain et les tumeurs cérébrales: une fonction autre que la régulation de la pression? [The renin-angiotensin system in human brain and brain tumors: a function unrelated to blood pressure control?]

The renin-angiotensin system (RAS), in addition to controlling blood pressure and the sodium-water balance, may be involved in cell growth and/or death in the brain. In order to address this issue, we compared the expression of RAS components in surgical specimens of human brain tumors and adjacent tissue. Human brain tumor cells and rat brain cells in culture were used to evaluate RAS functions. We found evidence that the RAS may be involved in maintaining the functions of the cerebral vasculature (the blood-brain-barrier) by controlling the ratio between angiotensin II and angiotensin III production, and by playing a more direct role in the survival of astroglial cells

Receptor-associated nuclear proteins and steroid/antisteroid action

* INRA, Biologie Cellulaire et Moleculaire, Jouy-en-JosasInternational audienc

Elevated blood pressure and heart rate in human renin receptor transgenic rats

Recently, a receptor for renin was described that may be important for vascular uptake and activation of (pro)renin, thus leading to local generation of angiotensin II. To assess the in vivo relevance of this protein, we generated transgenic rats overexpressing the human renin receptor gene in smooth muscle tissue, under the control of a 16-kb fragment of the mouse smooth muscle myosin heavy chain gene [TGR(SMMHC-HRR)]. Four lines of transgenic animals were obtained. The correct pattern of expression of the transgene was confirmed by RNase protection assay and in situ hybridization. TGR(SMMHC-HRR) rats are fertile and develop normally. After 6 months of age, transgenic rats develop a cardiovascular phenotype with an elevated systolic blood pressure (137.85 versus 118.93.7 mm Hg; P0.008), and an augmentation in heart rate (349.17.7 versus 303.116.16 bpm; P0.023) in TGR(SMMHC-HRR) and controls, respectively. These alterations are progressively increasing with aging. Although kidney function and plasma renin were normal in TGR(SMMHC-HRR), an increase in plasma aldosterone [TGR(SMMHC-HRR) 42864.9 versus 207.373.24 pg/mL in control; P0.02] and in aldosterone/renin ratio [TGR(SMMHC-HRR) 8.042.2 versus 2.80.55 in control; P0.03] was observed. This suggests that renin receptor overexpression has resulted in increased intraadrenal angiotensin II, thereby provoking enhanced aldosterone generation in the absence of changes in plasma renin. The rise in aldosterone may underlie, at least in part, the observed cardiovascular phenotype of TGR(SMMHC-HRR)

Angiotensinogen delays angiogenesis and tumor growth of hepatocarcinoma in transgenic mice.

International audienceAngiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo