The renin-angiotensin system (RAS) plays an important role in the regulation of arterial blood pressure and water and salt regulation. Until recently this system was considered to be exclusively a circulating endocrine system. Circulating renin, released by the renal juxtaglomerular cells, reacts with hepatically derived angiotensinogen (renin substrate) to form the inactive decapeptide angiotensin I (Ang 1). Ang I, in turn, is converted to the biologically active octapeptide angiotensin II (Ang II) by angiotensin converting enzyme (ACE) which is bound to the endothelial cell membrane. Ang II formed in the circulation diffuses to the tissues where it stimulates specific receptors on the surface of vascular smooth muscle cells as well as on the surface of the aldosterone-producing cells in the adrenal glands. More recent evidence, however, suggests that, in addition to the circulating endocrine RAS, there exist local or tissue renin-angiotensin systems in which Ang I and Ang II are formed in the tissues ratherthan in the circulation. Tissue production of these peptides may be catalyzed either by locally synthesized renin and renin substrate or by renin and renin substrate that are taken up from the plasma. Local renin-angiotensin systems have both autocrine and paracrinefunctions. Messenger RNA (mRNA) for renin has been demonstrated not only in the kidney but also in such organs as the adrenals, ovaries, testes, and brain, and mRNA for angiotensinogen has been found in all of these tissues as well. On the other hand, renin in the heart and blood vessel wall probably originates mainly in the kidneys and is then taken up from the circulation. Human plasma contains not only renin but also its enzymatically inactive precursor prorenin. Virtually all plasma renin is derived from the kidney, as evidenced by the observation that circulating renin levels are extremely low or not demonstrable in anephric patients. The kidney is also an important source of circulating prorenin. However the finding that anephric patients have plasma prorenin levels that are 30-40% of normal indicates that a proportion of circulating prorenin is clearly of extrarenal origin. It is likely that such organs as the adrenals, testes, and ovaries release not renin but prorenin into the circulation. For example, the increased plasma prorenin levels seen in pregnant women are largely derived from the ovaries. Unlike plama renin, plasma prorenin is increased in patients with diabetes mellitus who have microvascular complications. The mechanisms that account for the elevations in plasma prorenin levels seen in these patients are yet unknown. In patients receiving a beta-adrenoreceptor antagonist (beta-blocker), plasma renin levels fall and plasma prorenin levels rise. Thus, it has been proposed that the development of autonomic neuropathy in patients with diabetes mellitus may be responsible for the increase in plasma pro renin. Loss of sympathetic stimulation ofthe beta-adrenoreceptors on the juxtaglomerular cells might result in diminished secretion of renin and, as a compensatory mechanism, the synthesis and secretion of prorenin in the juxtaglomerular apparatus might be augmented According to an alternative hypothesis, when the juxtaglomerular cells are affected by diabetic micrangiopathy, conversion of prorenin to renin in these cells decreases and secretion of prorenin consequently increases

Additional Metadata
Keywords diabetes, drugs, endocrinology, prorenin, renine angiotensin system
Promotor M.A.D.H. Schalekamp (Maarten)
Publisher Erasmus University Rotterdam
Persistent URL
Franken, A.A.M. (1993, September 15). Prorenin and diabetes mellitus. Erasmus University Rotterdam. Retrieved from