An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model

Abstract

Angiotensin II type 1 receptor-associated protein (ATRAP) promotes AT1R internalization along with suppression of hyperactivation of tissue AT1R signaling. Here, we provide evidence that renal ATRAP plays a critical role in suppressing hypertension in a mouse remnant kidney model of chronic kidney disease. The effect of 5/6 nephrectomy on endogenous ATRAP expression was examined in the kidney of C57BL/6 and 129/Sv mice. While 129/Sv mice with a remnant kidney showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that downregulation of renal ATRAP expression is involved in pathogenesis of hypertension in the remnant kidney model of chronic kidney disease. Interestingly, 5/6 nephrectomy in ATRAP-knockout mice on the hypertension-resistant C57BL/6 background caused hypertension with increased plasma volume. Moreover, in knockout compared to wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel α-subunit and tumor necrosis factor-α was significantly enhanced, concomitant with increased plasma membrane angiotensin II type 1 receptor in the kidneys. Thus, renal ATRAP downregulation is involved in the onset and progression of blood pressure elevation caused by renal mass reduction, and implicates ATRAP as a therapeutic target for hypertension in chronic kidney disease.

5/6 nephrectomy induces different renal, cardiac and vascular consequences in 129/Sv and C57BL/6JRj mice

“…We found an increase of urinary aldosterone excretion after 5/6 Nx, which was similar between strains. Kobayashi et al 29…”

Transcripto‐based network analysis reveals a model of gene activation in tongue squamous cell carcinomas

“…Ang II type 1 receptor (AT1R)‐associated protein (ATRAP/Agtrap) is a transmembrane protein localized to the plasma membrane and perinuclear vesicular structures and was originally identified as a low‐molecular‐weight protein that binds to the carboxyl‐terminal domain of AT1R . The strongest expression of ATRAP was found in renal tubules of kidneys, and it also was found in the heart, kidneys, vascular smooth muscle cells, and adipose tissues .…”

“…21,22 The strongest expression of ATRAP was found in renal tubules of kidneys, and it also was found in the heart, kidneys, vascular smooth muscle cells, and adipose tissues. [22][23][24] Previous studies showed us that ATRAP could enhance the constitutive internalization of AT1R and suppress the activation of angiotensin II in order to negatively regulate angiotensin II signaling and selectively suppress Ang II-mediated pathological responses. 21 When the body is stimulated by various pathological factors such as highsodium diet and cardiovascular injury, the activation of angiotensin II could be suppressed by ATRAP, which can cause hypertension and organ dysfunction.…”

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

“…Furthermore, the quantitative analysis of immunofluorescence staining indicated that almost all of the internalized AT1R were associated with ATRAP, indicating that a major function of ATRAP in cultured cells including cardiovascular cells is to promote the constitutive internalization of AT1R [4,13,14]. Furthermore, a transgenic model increase in renal ATRAP expression beyond the baseline in vivo was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization in response to Ang II [15]. In contrast, a genetic deficient model of ATRAP caused an enhanced surface expression of AT1R in the kidney [16].…”