Enhanced Angiotensin Receptor-Associated Protein in Renal Tubule Suppresses Angiotensin-Dependent Hypertension

Abstract

We have previously shown that angiotensin II type 1 receptor-associated protein (ATRAP/Agtrap) interacts with the angiotensin II type 1 receptor and promotes constitutive internalization of the receptor so as to inhibit the pathological activation of its downstream signaling but preserve baseline physiological signaling activity. The present study was designed to investigate the role of renal ATRAP in angiotensin II–dependent hypertension. We generated transgenic mice dominantly expressing ATRAP in the renal tubules, including renal distal tubules. The renal ATRAP transgenic mice exhibited no significant change in blood pressure at baseline on normal salt diet. However, in the renal ATRAP transgenic mice compared with wild-type mice, the following took place: (1) the development of high blood pressure in response to angiotensin II infusion was significantly suppressed based on radiotelemetry, (2) the extent of daily positive sodium balance was significantly reduced during angiotensin II infusion in metabolic cage analysis, and (3) the renal Na+-Cl− cotransporter activation and α-subunit of the epithelial sodium channel induction by angiotensin II infusion were inhibited. Furthermore, adenoviral overexpression of ATRAP suppressed the angiotensin II–mediated increase in the expression of α-subunit of the epithelial sodium channel in mouse distal convoluted tubule cells. These results indicate that renal tubule–dominant ATRAP activation provokes no evident effects on blood pressure at baseline but exerts an inhibitory effect on the pathological elevation of blood pressure in response to angiotensin II stimulation, thereby suggesting that ATRAP is a potential target of interest in blood pressure modulation under pathological conditions.

Identifying multiple causative genes at a single GWAS locus

“…Of the six Agtrap-Plod1 genes, only three (Agtrap, Nppa, and Mthfr) were previously reported to have BP or renal phenotypes (John et al 1995;Yi and Li 2008;Wakui et al 2013), but none had been systematically examined in a uniform genetic background that is susceptible to hypertension. Using a ZFN rat strategy, we found that Nppa, Clcn6, Mthfr, Plod1, and Agtrap mutations caused divergent CVD phenotypes and have the ability to modify renal phenotypes independently of BP (Fig.…”

Angiotensin II Type 1 Receptor–associated Protein

“…Finally and most importantly, the fact that a very high ATRAP expression (33-fold mRNA increase in distal tubules and 10-fold protein increases in total kidney homogenates) was necessary to reduce the response to Ang II suggests that ATRAP effects may be minor. Regardless of the previous observations, the study by Wakui et al 5 emphasizes the tremendous impact of the kidneys in the hypertensive response to Ang II, while highlighting the potential of ATRAP as a negative modulator. The authors present interesting evidence for the tuning down effect of ATRAP on Ang II actions to increase sodium avidity in the nephron.…”

“…Detailed analysis of renal ATRAP expression in their mutant strain revealed that distal regions of the nephron, from the distal to connecting tubules, were the sites of highest expression for the transgenic protein. The most important observation by Wakui et al 5 is that ATRAP overexpression in the distal nephron blunted the pressor response to Ang II. In their experiments, the basal systolic blood pressure of the transgenic mice and wild-type mice was similar.…”

“…In this issue of Hypertension, Wakui et al 5 analyzed the responses to Ang II infusion of transgenic mice overexpressing ATRAP predominantly in the distal nephron. Detailed analysis of renal ATRAP expression in their mutant strain revealed that distal regions of the nephron, from the distal to connecting tubules, were the sites of highest expression for the transgenic protein.…”

“…Although Oppermann et al 4 reported that ATRAP is mostly expressed in the proximal tubule, the studies from Umemura's group suggest a more extensive distribution. 5,8 According to these authors, endogenous ATRAP is expressed in glomeruli, vasculature, proximal, and distal segments of the nephron.…”