Intrarenal suppression of angiotensin II type 1 receptor binding molecule in angiotensin II-infused mice

Abstract

ATRAP [ANG II type 1 receptor (AT1R)-associated protein] is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous ANG II infusion on the intrarenal expression and distribution of ATRAP and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1,000, or 2,500 ng·kg(-1)·min(-1) for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2,500 ng·kg(-1)·min(-1)) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and the α-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng·kg(-1)·min(-1)), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.

13-cis-Retinoic acid specific down-regulation of angiotensin type 1 receptor in rat liver epithelial and aortic smooth muscle cells

“…Numerous studies have shown that alterations in AT1 expression leading to altered regulation of downstream intracellular modulators dictate specific patterns in downstream effectors; however, the role of these intracellular modulators on AT1 transcription remains enigmatic (Bonde et al 2010, Wakui et al 2010, Ozawa et al 2011. In this study, we examined the effect of 13cRA on the expression of AT1 in rat liver epithelial cells known to express the native protein.…”

Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats

“…The characterization and specificity of the anti-ATRAP antibody and the anti-AT1R antibody (sc-1173; Santa Cruz Biotechnology Inc., Santa Cruz, California, USA) were described previously [19,20,25,26]. The antip22phox antibody (sc-20781; Santa Cruz Biotechnology Inc.), anti-p47phox antibody (sc-14015; Santa Cruz Biotechnology, Inc.), anti-Rac1 antibody (DAM1522857; Millipore) and anti-Ang II type 2 receptor (AT2R) antibody (sc-9040; Santa Cruz Biotechnology Inc.) were also used in this study.…”

“…The antip22phox antibody (sc-20781; Santa Cruz Biotechnology Inc.), anti-p47phox antibody (sc-14015; Santa Cruz Biotechnology, Inc.), anti-Rac1 antibody (DAM1522857; Millipore) and anti-Ang II type 2 receptor (AT2R) antibody (sc-9040; Santa Cruz Biotechnology Inc.) were also used in this study. Western blot analysis was performed essentially as described [19,20,25,26].…”

“…We showed that there is a tissuespecific regulatory balancing of the expression of ATRAP and AT1R during the development of hypertension in spontaneously hypertensive rats (SHRs) [19]. The activation of ATRAP in transgenic-models in which ATRAP expression was increased beyond baseline promoted Ang II-mediated AT1R internalization and inhibited renal angiotensinogen production and cardiac hypertrophy in response to Ang II stimulation [20].…”

An increase in perfusion pressure and activation of the renin–angiotensin system in the pathogenesis of hypertension and injury: strain vessels and the cerebrovascular-renal connection

“…Our previous studies also revealed that there was significant suppression of endogenous ATRAP expression in the renal inner cortex and outer medulla concomitant with the development of Ang II-mediated hypertension and salt-sensitive hypertension. 19,20 A previous study showed that as SHR-SP rats developed hypertension, the genes encoding components of the reninangiotensin system were expressed at higher levels in the kidney 21 ; therefore, it was proposed that the intrarenal reninangiotensin system is activated by this type of genetic hypertension. Thus, further investigations are warranted to examine the possible role of renal ATRAP in the pathophysiology of hypertension and renal injury, including albuminuria and the production of oxidative stress-related molecules, in SHR-SP rats (Figure 1).…”