Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.
Renin is an aspartyl protease essential for the control of blood pressure and was long suspected to have cellular receptors. We report the expression cloning of the human renin receptor complementary DNA encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of MAP kinases ERK1 and ERK2. High levels of the receptor mRNA are detected in the heart, brain, placenta, and lower levels in the kidney and liver. By confocal microscopy the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery, associated to smooth muscle cells and colocalized with renin. The renin receptor is the first described for an aspartyl protease. This discovery emphasizes the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II.
Nguyen
Genevieve
G
Institut National de la Santé et de la Recherche Médicale (INSERM) U489, and Association Claude Bernard, Hopital Tenon, Paris, France. genevieve.nguyen@tnn.ap-hop-paris.fr
Delarue
Françoise
F
Burcklé
Céline
C
Bouzhir
Latifa
L
Giller
Thomas
T
Sraer
Jean-Daniel
JD
D000595:Amino Acid Sequence; D000803:Angiotensin I / Q000096:biosynthesis; D000804:Angiotensin II / Q000096:biosynthesis*; D001483:Base Sequence; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D003001:Cloning, Molecular; D003432:Cross-Linking Reagents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D015723:Gene Library; D005920:Glomerular Mesangium / Q000166:cytology; D006801:Humans; D007700:Kinetics; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D012083:Renin / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014162:Transfection; D025262:Vacuolar Proton-Translocating ATPases; D000093342:Prorenin Receptor
D000803:Angiotensin I; D000804:Angiotensin II; D002118:Calcium; D003432:Cross-Linking Reagents; D000242:Cyclic AMP; D004247:DNA; D004792:Enzyme Precursors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor