Intracellular Renin and the Nature of Intracrine Enzymes

Abstract

Abstract-Recently, the binding of renin and prorenin to cellular receptors with the subsequent generation of second messengers and the production of physiological effects has been demonstrated. In addition, the internalization of prorenin by target cells has been associated with increased cellular synthesis of angiotensin and cardiac pathology. Also, a renin transcript lacking the sequences encoding a secretory signal has been reported, and this transcript appears to produce a renin that acts in the cell that synthesized it. Some years ago, we coined the term intracrine for a peptide hormone or factor that acts in the intracellular space either after internalization or retention in its cell of synthesis. Thus defined, a wide variety of peptides display intracrine functionality, including hormones, growth factors, transcription factors, and enzymes. For example, considerable evidence indicates that angiotensin II is an intracrine. Also, general principles of intracrine functionality have been developed. Thus, recent evidence demonstrates that the prorenin/renin molecule is an intracrine enzyme. Here, the actions of intracrine enzymes (angiogenin, phosphoglucose isomerase, phospholipase A2, granzyme A and B, thioredoxin, platelet-derived endothelial growth factor, and serine protease inhibitors) are reviewed. Key Words: renin Ⅲ platelet-derived growth factor Ⅲ enzymes Ⅲ angiotensin II Ⅲ phospholipases R enin gene expression leads to the synthesis of prorenin in the juxtaglomerular cells of the kidney, activation and secretion of renin by these cells, the generation of angiotensin I by renin enzymatic activity, and the subsequent generation of angiotensin II either in the plasma or tissues. However, renin, angiotensin I, and angiotensin II can also be taken up by tissues with subsequent enzymatic conversions occurring locally. Moreover, there is considerable evidence, both in animal models and in humans, in favor of the local synthesis of each of the components of the renin-angiotensin system (RAS) in various tissues leading to locally determined angiotensin generation. 1 In addition to evidence indicating local synthesis and uptake in tissues of RAS components, there is growing evidence to indicate the uptake and synthesis of components of the RAS by individual cells, thereby suggesting a new arena for the action of this physiological system. 2 Important among these new observations are studies demonstrating that (1) prorenin and renin can bind to specific cellular receptors with the generation of physiological effects, (2) prorenin, and to a lesser extent, renin, can be internalized by cells whereupon angiotensin II is produced, and (3) there exists a renin transcript in some cells that encodes a renin that is expected to be synthesized as an active, as opposed to a prorenin, and that is expected to remain in the cell because it lacks the sequence encoding the secretory signal piece (renin exon 1A). 2-13 These observations not only reveal prorenin and renin to be hormones in their own right, they suggest that pro...

Direct renin inhibition: extricating facts from façades

“…Alternatively, local renin production takes place in the kidney, ovary, brain, uterus and others organs [Re, 2001[Re, , 2003a[Re, , 2003bPaul et al 2006]. A putative role for this local RAS is sustained by a number of theoretical estimates and experimental evidence.…”

Intercellular Communication

“…Prorenin and renin can bind to specific cellular receptors. Prorenin, and to a lesser extent, renin, can be internalized by cells where angiotensin II is produced (Re, 2003a). Internalized, activated prorenin causes both hypertension and cardiac injury.…”

Review: Angiotensin Peptides and their Pleiotropic Actions

“…6 These observations raised the possibility that a complete intracellular RAS can exist in some tissues.…”

“…16 The actions of both ACE1 and its homologue ACE2 seem to be more complex than originally believed. Beside their function as key regulators within RAS, they also hydrolyze some other peptide substrates (des-Arg-bradykinin, neurokinins, apelin, dynorphin A [1][2][3][4][5][6][7][8][9][10][11][12][13] ). The precise interplay between tissue ACE1, ACE2 and their substrates and by-products are still unclear.…”