Active renin (Angiotensinogenase, REN)

Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS), which primarily acts to control blood pressure and sodium balance. RAAS activity is also involved in angiogenesis, cellular growth, fibrosis, reproduction, inflammation, immunity, intracellular redox balance and antidiuretic hormone production. The active enzyme renin is a specific aspartyl protease with molecular weight of 37 kDa and is responsible for the cleavage of angiotensinogen produced in the liver into angiotensin I which is further converted into active angiotensin II in the vascular epithelium of the lung. Renin is produced in juxtaglomerular (JG) cells of the kidney as the inactive precursor prorenin in which the prosegment region with 43 amino acid residues covers the active site of renin. Cleavage of the prosegment converts prorenin to active (mature) renin, and JG cells are the only known sites where prorenin is converted to renin proteolytically. Non-proteolytic activation occurs when prosegment is unfolded from enzymatic cleft, thus allowing intact prorenin to become catalytically active. This process occurs under acidic pH and low temperature or after binding of prorenin to renin receptor. The (pro)renin receptor is expressed in many organs, thus, it may help to accumulate renin and prorenin locally and activate tissue-specific renin-angiotensin systems (RAS). Locally expressed RAS was found in a number of tissues, including the kidney, adrenal gland, heart, vasculature and nervous system, under different physiological and pathophysiological conditions. Local RAS has a variety of functions, including local cardiovascular regulation, in association with or independently of the systemic RAS, as well as non-cardiovascular functions and influences cell growth, differentiation, apoptosis, etc. Active renin is stored in granules of the JG cells and is released by an exocytic process into the kidney and then into systemic circulation. Renin secretion is stimulated by a fall in perfusion pressure or in NaCl delivery to the distal tubules and by an increase in sympathetic activity, in contrast to prorenin which is secreted into blood constitutively. Prorenin level in the circulation is about 10 times higher than that of mature renin. Renin has also been identified in urine and amniotic fluid. Control of renin secretion is the key determinant of the RAAS and renin’s chronic activation is the major contributing factor to pathogenesis and progression of cardiovascular and renal disorders. RAAS directly affects vascular and cardiac remodeling through proliferative and inflammatory signaling. Blockers of systemic RAS play a prominent role in the treatment of arterial hypertension, heart failure, diabetes and nephropathy. The clinical application of renin inhibitor therapy has stimulated new interest in the measurement of renin and its precursor prorenin. Measurement of plasma active renin is important for differential diagnosis of hypertension, clinical assessment of hypertensive patients and for diagnostics of insufficient response to antihypertensive treatment. The ratio of aldosterone to renin concentration should be useful for screening patients suspected of primary aldosteronism. Study of the relationship of plasma renin levels to renal function in patients with primary aldosteronism indicated that the lack of suppression of renin by excess aldosterone is associated with more severe renal damage and predicts less favorable outcomes after treatment. Urine renin reflects the renal RAAS activity in the kidney and thus may reflect success of RAAS blockade in the kidney during RAAS blocker therapy in patients with diabetic as well as non-diabetic nephropathy. Other clinical implications of active renin measurement involve diagnosis of isolated deficit in mineral corticoids, detection of renin producing tumor in kidney, or monitoring of glucocorticoid therapy.