MOLECULAR CHARACTERIZATION OF ANGIOTENSIN II RECEPTORS

血管紧张素II是肾素-血管紧张素原衍生的八肽

Angiotensin II is an octapeptide derived from the renin-angiotinsenogen system which evokes a broad spectrum of effects related to regulation of blood pressure and to salt and water metabolism. Indeed, the most effective therapeutic agent for human hypertension acts by blocking the formation of angiotensin II. The broad, long-term objective of the proposed studies is the molecular characterization of angiotensin II receptors. The specific objective of this application is the study of an apparently new form of the angiotensin II, type 1 receptor molecularly cloned from the rat anterior pituitary gland. This clone differs from the angiotensin II, type 1 receptor recently described for vascular smooth muscle and kidney. The pituitary form of the receptor has an overall 74% identity at the nucleotide level with the vascular/kidney receptor; however, it encodes a protein with a 95% amino acid identity. The differences in the two forms of receptors are not consistent with alternative RNA splicing suggesting that the pituitary and vascular/renal receptors are encoded by separate genes. The ligand binding characteristics of the two forms of receptors are similar. Their tissue mRNA expression differs somewhat in that the pituitary and vascular smooth muscle show the highest levels of their cognate receptors. Finally, pituitary levels of mRNA are strongly regulated by estrogens. The Specific Aims of the proposal are to: 1) compare the ligand-binding characteristics of the two forms of receptors; 2) identify the second messenger system utilized by the pituitary form of the receptor; 3) determine the differential tissue distribution of mRNAs encoding the two forms of receptors; 4) test the effects of estrogens on mRNA expression of the two forms of receptors in various tissues; 5) clone, sequence, and characterize the gene encoding the pituitary form of the receptor; 6) isolate, sequence, and characterize the human form of the pituitary receptor; 7) determine the cell localization of the two forms of receptor mRNA using in situ hybridization, and; 8) produce monoclonal antibodies to peptides derived from the two forms of receptors. These studies should provide new information about the etiology and treatment of human hypertension.