Abstract P202: Angiotensin Receptor-binding Protein ATRAP as a Possible Candidate for Therapeutic Strategy of Functionally Selective Modulation of Angiotensin Receptor Signaling
Drug discovery targeting GPCRs is no longer limited to seeking agonists or antagonists to stimulate or block cellular responses associated with a particular receptor. GPCRs are now known to support a diversity of pharmacological profiles, a concept broadly referred to as functional selectivity. Therefore, if possible, functionally selective modulation of receptor signaling may be a safer, better tolerated, and more efficacious therapeutic strategy. Recent research progress is reported in the field of functional selectivity such as receptor biased ligands, and receptor binding molecules for the therapy of cardiovascular and renal pathophysiology.
The renin-angiotensin system including plays a critical role in the regulation of cardiovascular and renal function in physiological homeostasis via activity of its effector AT1R. While exaggerated activation of AT1R promotes organ damages by BP elevation and insulin resistance via enhancement of oxidative stress, inflammation and fibrotic response, genetic total inactivation of the renin-angiotensin system components, such as angiotensinogen, renin and AT1R, reportedly results in significant hypotension and in renal morphological alteration even under baseline condition from birth, indicating that baseline AT1R signaling activity is indispensable for the maintenance of cardiovascular and renal physiology.
In the course of an investigational search for a sophisticated means to regulate AT1R signaling at local tissue sites, we have focused our analysis on the AT1R-associated protein (ATRAP; Agtrap gene), which is a molecule that directly binds to the carboxyl[[Unable to Display Character: ‐]]terminal domain of AT1R. In contrast to the classical components of the renin-angiotensin system (i.e. angiotensinogen, renin and AT1R), alteration of ATRAP expression exerts no evident effects on baseline BP and renal morphology in vivo such as in ATRAP-transgenic mice and ATRAP-deficient mice. However, accumulating results in these mice indicate that ATRAP exerts inhibitory effects on the exaggerated activation of tissue AT1R signaling in response to pathological stimuli, in order to protect cardiovascular and renal tissues under pathological stimuli, in spite of no influence of ATRAP on physiological AT1R signaling.
Author Disclosures: K. Tamura: None. H. Wakui: None. K. Azushima: None. K. Uneda: None. R. Kobayashi: None. K. Ohki: None. S. Haku: None. K. Haruhara: None. S. Kinguchi: None. M. Ohsawa: None. A. Maeda: None. T. Kanaoka: None. S. Umemura: None.
- © 2015 by American Heart Association, Inc.