Losing Control: Positive and Negative Feedback in the Renin Angiotensin System

The renin angiotensin system (RAS) is a key homeostatic regulator that relies on feedback regulation to achieve and sustain the delicate balance required for healthy physiological function. A number of negative feedback loops exist within the RAS that counterbalance the effects of conventional RAS blockade. Indeed, instead of reducing levels of Ang II and aldosterone, exaggerated feedback responses lead to a paradoxical elevation in many patients treated with RAS blockers. This ‘escape’ has been used to explain a number of clinically-relevant phenomena including progressive left ventricular hypertrophy, deteriorating cardiac and renal function in the face of full-dose RAS blockade. Escape has been thought to be mediated by reactive increases in renin activity and Ang I, which is then converted to Ang II, via non- ACE pathways (or by ACE when inhibitors are cleared). The reduced expression and activity of the angiotensinase Angiotensin Converting Enzyme 2 (ACE2) following RAS blockade may have a role. Bystander activation of the uninhibited AT2 receptor during long-term angiotensin receptor blockade (ARB) can also increase aldosterone synthesis. Feed forward or positive feedback loops also exist within the RAS, which exaggerate the effects of signaling and contribute to progressive hypertension and vascular damage. For example, Ang II acts to increase the expression of angiotensinogen in the kidney and the liver. The strong association between adverse outcomes and activation of feedback pathways provide a strong rationale for specifically targeting feedback as part of any vasculo-protective strategy.