Angiotensin II increases differentiation of dopaminergic neurons from mesencephalic precursors via angiotensin type 2 receptors

• Published in: The European journal of neuroscience Vol. 20; no. 6; pp. 1489 - 1498
• Main Authors: Rodriguez-Pallares, J., Quiroz, C. R., Parga, J. A., Guerra, M. J., Labandeira-Garcia, J. L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.09.2004
• Subjects: Angiotensin II - pharmacology; Angiotensin II Type 2 Receptor Blockers; Animals; Apoptosis - drug effects; Bromodeoxyuridine - pharmacokinetics; Cell Count - methods; Cell Differentiation - drug effects; Cells, Cultured; dopamine; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Drug Interactions; Embryo, Mammalian; Glial Fibrillary Acidic Protein - metabolism; Imidazoles - pharmacology; Immunoblotting - methods; Immunohistochemistry - methods; In Situ Nick-End Labeling - methods; Membrane Glycoproteins - metabolism; Membrane Transport Proteins - metabolism; Mesencephalon - cytology; Naphthyridines - pharmacology; Nerve Tissue Proteins - metabolism; Neurons - metabolism; Parkinson's disease; Phosphopyruvate Hydratase - metabolism; progenitor cells; Pyridines - pharmacology; rat; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Angiotensin, Type 2 - physiology; Stem Cells - physiology; transplantation; Tubulin - metabolism; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2004.03621.x

In addition to the well‐known actions of the humoral renin–angiotensin system, all components of this system are present in many tissues, including the brain, and may play a major role in brain development and differentiation. We investigated the possible effects of angiotensin II on the generation of dopaminergic phenotype neurons from proliferating neurospheres of mesencephalic precursors. We observed immunoreactivity for both angiotensin type 1 and type 2 (AT1 and AT2) receptors in the cell aggregates. Double immunolabeling studies revealed that both receptor types are located in neurons and astrocytes. Interestingly, neurons with a dopaminergic phenotype (i.e. tyrosine hydroxylase activity) showed double labeling for AT1 and AT2 receptors although the labeling for AT2 was more intense. Treatment of the neurospheres with angiotensin II (100 nm) during the differentiation period induced a marked increase (about 400%) in the generation of dopaminergic neurons. This was not affected by treatment with the AT1 antagonist ZD 7155 but was blocked by treatment with the AT2 antagonist PD 123319. This suggests that AT2 receptors mediate the stimulatory effect of angiotensin II on the generation of dopaminergic neurons. Apoptotic cell death studies and bromodeoxyuridine immunohistochemistry indicated that the increase in generation of dopaminergic neurons is not due to increased survival or proliferation of dopaminergic cells during treatment with angiotensin and suggested that angiotensin induces increased differentiation of mesencephalic precursors towards the dopaminergic phenotype. Manipulation of the renin–angiotensin system may be useful for increasing production of dopaminergic neurons for transplantation in Parkinson's disease.