Renal Tubule Angiotensin II Type 1 Receptor–Associated Protein Promotes Natriuresis and Inhibits Salt‐Sensitive Blood Pressure Elevation

<jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> Angiotensin <jats:styled-content style="fixed-case">II</jats:styled-content> type 1 receptor ( <jats:styled-content style="fixed-case">AT</jats:styled-content> 1R)–associated protein ( <jats:styled-content style="fixed-case">ATRAP;</jats:styled-content> <jats:italic>Agtrap</jats:italic> gene) promotes <jats:styled-content style="fixed-case">AT</jats:styled-content> 1R internalization along with suppression of pathological <jats:styled-content style="fixed-case">AT</jats:styled-content> 1R activation. In this study, we examined whether enhancement of <jats:styled-content style="fixed-case">ATRAP</jats:styled-content> in the renal distal tubules affects sodium handling and blood pressure regulation in response to high salt ( <jats:styled-content style="fixed-case">HS</jats:styled-content> ) loading, using <jats:styled-content style="fixed-case">ATRAP</jats:styled-content> transgenic mice on a salt‐sensitive C57 <jats:styled-content style="fixed-case">BL</jats:styled-content> /6J background. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> Renal <jats:styled-content style="fixed-case">ATRAP</jats:styled-content> transgenic ( <jats:styled-content style="fixed-case">rATRAP</jats:styled-content> ‐Tg) mice, which exhibit renal tubule–dominant <jats:styled-content style="fixed-case">ATRAP</jats:styled-content> enhancement, and their wild‐type littermate C57 <jats:styled-content style="fixed-case">BL</jats:styled-content> /6J mice on a normal salt diet (0.3% NaCl) at baseline were subjected to dietary <jats:styled-content style="fixed-case">HS</jats:styled-content> loading (4% NaCl) for 7 days. In <jats:styled-content style="fixed-case">rATRAP</jats:styled-content> ‐Tg mice, the dietary <jats:styled-content style="fixed-case">HS</jats:styled-content> loading–mediated blood pressure elevation was suppressed compared with wild‐type mice, despite similar baseline blood pressure. Although renal angiotensin <jats:styled-content style="fixed-case">II</jats:styled-content> level was comparable in <jats:styled-content style="fixed-case">rATRAP</jats:styled-content> ‐Tg and wild‐type mice with and without <jats:styled-content style="fixed-case">HS</jats:styled-content> loading, urinary sodium excretion in response to <jats:styled-content style="fixed-case">HS</jats:styled-content> loading was significantly enhanced in the <jats:styled-content style="fixed-case">rATRAP</jats:styled-content> ‐Tg mice. In addition, functional transport activity of the amiloride‐sensitive epithelial Na <jats:sup>+</jats:sup> channel was significantly decreased under saline volume–expanded conditions in <jats:styled-content style="fixed-case">rATRAP</jats:styled-content> ‐Tg mice compared with wild‐type mice, without any evident change in epithelial Na <jats:sup>+</jats:sup> channel protein expression. Plasma membrane <jats:styled-content style="fixed-case">AT</jats:styled-content> 1R expression in the kidney of <jats:styled-content style="fixed-case">rATRAP</jats:styled-content> ‐Tg mice was decreased compared with wild‐type mice. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> These results demonstrated that distal tubule–dominant enhancement of <jats:styled-content style="fixed-case">ATRAP</jats:styled-content> inhibits pathological renal sodium reabsorption and blood pressure elevation in response to <jats:styled-content style="fixed-case">HS</jats:styled-content> loading. The findings suggest that <jats:styled-content style="fixed-case">ATRAP</jats:styled-content> ‐mediated modulation of sodium handling in renal distal tubules could be a target of interest in salt‐sensitive blood pressure regulation. </jats:p> </jats:sec>