Unraveling the Physiology of (Pro)Renin Receptor in the Distal Nephron
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The classic renin–angiotensin system (RAS) is a well-defined endocrine system consisting of liver production of angiotensinogen, which is converted to angiotensin I by renin followed by a second cleavage to angiotensin II (AngII) by angiotensin-converting enzyme located on the surface of lung endothelium.1,2 AngII is the major effector hormone of the RAS, playing a key role in the maintenance of extracellular volume, blood pressure, renal hemodynamics, and tubular sodium transport, as well as in the pathogenesis of cardiovascular and renal diseases.3–5 AngII acts on 2 types of membrane receptors, AngII type 1 receptor and type 2 receptor. The RAS interventions targeting AngII type 1 receptor and angiotensin-converting enzyme are widely used for management of hypertension, renal disease, and cardiovascular disease. During the past several decades, the RAS has evolved into a highly complex system as highlighted by the discovery of angiotensin-converting enzyme 2/Ang 1 to 7/Mas pathway and the local RAS found in several tissues, such as the kidney, the heart, and the brain.1,6,7 The RAS activity is largely controlled by renin-mediated conversion of angiotensinogen to Ang I, a rate-limiting step in the RAS. Renin is a protease produced by juxtaglomerular cells of the afferent arteriole as well as collecting duct (CD) principal cells,8 mast cells,9 adipocytes,10 etc. Prorenin, a precursor of renin, contains a prosegment covering the catalytic domain and undergoes proteolytic cleavage to generate the mature renin. Plasma prorenin levels are elevated in diabetic patients and predict microvascular complications, whereas plasma renin is normal or low.11 Animal data suggests that excess prorenin compared with active renin in diabetes mellitus originates from the CD rather than from the juxtaglomerular apparatus.12 High prorenin state is also seen in normal pregnancy.13,14