Characterization of a functional (pro)renin receptor in rat brain neurons.
(Pro)renin receptor (PRR), the newest member of the renin-angiotensin system (RAS), is turning out to be an important player in the regulation of the cardiovascular system. It plays a pivotal role in activation of the local RAS and stimulates signalling pathways involved in proliferative and hypertrophic mechanisms. However, the role of PRR in the brain remains unknown. Thus, our objective in this study was to determine whether a functional PRR is present in neurons within the brain. Neuronal co-cultures from the hypothalamus and brainstem areas of neonatal rat brain express PRR mRNA. Immunoreactivity for PRR was primarily localized on the neuronal cell soma and in discrete areas in the neurites. Treatment of neurons with renin, in the presence of 2 microm losartan, caused a time- and dose-dependent stimulation of phosphorylation of extracellular signal related kinase ERK1 (p44) and ERK2 (p42) isoforms of mitogen-activated protein kinase. Optimal stimulation of fourfold was observed within 2 min with 20 nm renin. Electrophysiological recordings showed that treatment of the neurons with renin, in the presence of 2 microm losartan, resulted in a steady and stable decrease in action potential frequency. A 46% decrease in action potential frequency was observed within 5 min of treatment and was attenuated by co-incubation with a PRR blocking peptide. These observations demonstrate that the PRR is present in neurons within the brain and that its activation by renin initiates the MAP kinase signalling pathway and inhibition of neuronal activity.
Shan
Zhiying
Z
Department of Physiology and Functional Genomics, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
Cuadra
Adolfo E
AE
Sumners
Colin
C
Raizada
Mohan K
MK
D000200:Action Potentials / Q000187:drug effects; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology; D001923:Brain Chemistry / Q000502:physiology*; D002478:Cells, Cultured; D004594:Electrophysiology; D007150:Immunohistochemistry; D019808:Losartan / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011921:Rats, Inbred WKY; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D000093342:Prorenin Receptor
D047228:Angiotensin II Type 1 Receptor Blockers; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019808:Losartan; D000093342:Prorenin Receptor