Expanding Saga of the Renin-Angiotensin System

The search for hidden truths behind established concepts and dogma is often a never-ending, uphill climb and the history of Science and Medicine is full of examples of this. " To raise new questions, new possibilities, to regard old questions from a new angle, requires creative imagination and marks real advances in science " (Albert Einstein). The story of the renin-angiotensin system (RAS), hypertension and kidney disease began nearly two centuries ago,1 with report of a clinico-pathophysiologic study of albuminuria in patients followed by Goldblatt's induction of hypertension in experimental dogs in the 1930's.2 It took seven more decades of basic, translational and clinical research to discover the pressor effect of renal extracts (ascribed to renin) in 1898 and another ten decades of imaginative work by many to culminate in the discovery of angiotensin-II (Ang-II), the primary effector peptide of the RAS, and its receptors (AT1R and AT2R) in 2000.3 Since then, expansion of the RAS to the renin-angiotensin-aldosterone (RAAS) system and discovery of several bioactive peptides produced through Ang-II degradation has contributed to the increasing complexity of the RAS (Figures 1A and1B) and the search continues.