The tissue renin-angiotensin system and intracellular signalling

The renin-angiotensin system is not what it was, or for that matter not necessarily where we thought it should be. For example, there is a novel angiotensin I-metabolizing enzyme that generates angiotensin 1-7 rather than angiotensin II. Moreover, we are slowly realizing the importance of local rather than circulating angiotensin II.

Rather than concentrating on the systemic renin-angiotensin system, recent work has concentrated on elucidating the consequences of increasing angiotensin II production within specific organs, such as the heart and vasculature, as well as in the pancreas and in adipose tissue. Inhibition of angiotensin II production either using angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers not only reverses remodelling but also increases tissue insulin sensitivity. Targeting the renin-angiotensin system clinically delays the onset of type 2 diabetes, but the mechanisms involved are not clearly understood. Moreover, at least one other angiotensin-converting enzyme homologue (ACE2) plays a significant role in the regulation of heart and kidney function, and as it generates angiotensin 1-7 from angiotensin I, it is proposed to counteract the detrimental effects associated with the activation of the classic renin-angiotensin system.

There is a need to re-evaluate the role(s) played by the molecular components of the "extended" local renin-angiotensin system and their role in vascular disease and type 2 diabetes.