Angiotensin II increases differentiation of dopaminergic neurons from mesencephalic precursors via angiotensin type 2 receptors.
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 (AT(1) and AT(2)) 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 AT(1) and AT(2) receptors although the labeling for AT(2) 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 AT(1) antagonist ZD 7155 but was blocked by treatment with the AT(2) antagonist PD 123319. This suggests that AT(2) 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.
Rodriguez-Pallares
J
J
Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Quiroz
C R
CR
Parga
J A
JA
Guerra
M J
MJ
Labandeira-Garcia
J L
JL
D000804:Angiotensin II / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology*; D009287:Naphthyridines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D014404:Tubulin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D057912:Angiotensin II Type 2 Receptor Blockers; D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D007093:Imidazoles; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009287:Naphthyridines; D009419:Nerve Tissue Proteins; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014404:Tubulin; C095905:ZD 7155; D000804:Angiotensin II; C073402:PD 123319; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine; D004298:Dopamine