Angiotensin II Short-Loop Feedback: Is There a Role of Ang II for the Regulation of the Renin System In Vivo?

The activity of the renin-angiotensin-aldosterone system is triggered by the release of the protease renin from the kidneys, which in turn is controlled in the sense of negative feedback loops. It is widely assumed that Ang II (angiotensin II) directly inhibits renin expression and secretion via a short-loop feedback by an effect on renin-producing cells (RPCs) mediated by AT1 (Ang II type 1) receptors. Because the concept of such a direct short-loop negative feedback control, which originates mostly from in vitro experiments, has not yet been systematically proven in vivo, we aimed to test the validity of this concept by studying the regulation of renin synthesis and secretion in mice lacking Ang II-AT1 receptors on RPCs. We found that RPCs of the kidney express Ang II-AT1 receptors. Mice with conditional deletion of Ang II-AT1 receptors in RPCs were normal with regard to the number of renin cells, renal renin mRNA, and plasma renin concentrations. Renin expression and secretion of these mice responded to Ang I (angiotensin I)-converting enzyme inhibition and to Ang II infusion like in wild-type (WT) controls. In summary, we did not obtain evidence that Ang II-AT1 receptors on RPCs are of major relevance for the normal regulation of renin expression and secretion in mice. Therefore, we doubt the existence of a direct negative feedback function of Ang II on RPCs.