The pathophysiological role of angiotensin receptor-binding protein in hypertension and kidney diseases: Oshima Award Address 2019

Excessive activation of the tissue renin–angiotensin system through angiotensin II (Ang II) type 1 receptor (AT1R) plays a pivotal role in the pathogenesis of hypertension and related organ injury. AT1R-associated protein (ATRAP/Agtrap) was identified as a molecule specifically interacting with the carboxyl- terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R including kidney. The results of in vivo study employing genetic engineered mice with modified ATRAP expression showed that ATRAP inhibits cardiovascular injuries provoked by Ang II-induced hypertension, along with preserving physiological AT1R signaling. In addition, we have shown that ATRAP functions as an endogenous modulator so as to prevent hypertension in response to pathological stimuli, by regulating renal sodium handling. Furthermore, ATRAP may have an AT1R-independent function of renal proximal tubule to protect aging and fibrosis. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and cardiorenal and vascular diseases.