Abstract 14881: Prepubertal Blockade of Angiotensin II Type 1 Receptor Causes Long-term Therapeutic Effects through Sustained Enhancement of Renal ATRAP Expression in Dahl Salt-sensitive Hypertensive Rats
Activation of angiotensin II (Ang II) type 1 receptor (AT1 receptor) signaling plays a pivotal role in the pathogenesis of hypertension and renal injury. We cloned a novel molecule interacting with AT1 receptor, which we named ATRAP (for AT1 receptor-associated protein). Previous studies showed that ATRAP promotes constitutive internalization of AT1 receptor and further attenuates Ang II-mediated pathological responses in cultured cells. In this study we examined whether the regulation of renal ATRAP expression in vivo is related to the development of hypertension and renal injury and the therapeutic effects of AT1 receptor blocker (ARB) in salt-sensitive hypertension. Dahl salt-sensitive hypertensive rats (DS rats, 3 wks of age) were divided into three groups for oral administration of vehicle (vehicle group) or olmesartan (8 mg/kg per day) either continuously from 6 to 16 wks of age (continuous ARB group) or transiently from weaning to puberty (3 to 10 wks of age, prepubertal ARB group) and fed high salt diet (8% NaCl) from 6 to 16 wks of age. DS rats fed a normal salt diet (0.3% NaCl) were used as controls (control group). Not only continuous ARB treatment (SBP 149±9 mmHg) but also prepubertal ARB treatment (SBP 142±7 mmHg) significantly improved hypertension at 16 wks of age with reduction of urinary protein excretion, as compared to vehicle group (SBP 199±15 mmHg). With respect to the regulation of ATRAP expression in the kidney, the renal ATRAP expression was significantly suppressed in vehicle group compared with control group on immunohistochemistry and western blot analysis (relative ATRAP protein level, 100 vs 80%, P<0.05), concomitant with upregulation of renal p22-phox protein expression (100 vs 150%, P<0.05). However, prepubertal ARB treatment as well as continuous ARB treatment significantly recovered the suppressed renal ATRAP expression and inhibited the renal p22-phox activation. These results indicate that the prepubertal blockade of AT1 receptor signaling is able to exert a long-term therapeutic effect on hypertension and renal injury, at least partly, through sustained enhancement of renal ATRAP expression in Dahl salt-sensitive hypertensive rats, thereby suggesting ATRAP to be a novel molecular target in hypertension and renal injury.
- © 2010 by American Heart Association, Inc.