Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence.

Abstract

A comprehensive review of physiological and molecular biological evidence refutes claims for synthesis of renin by cardiac and vascular tissues. Cardiovascular tissue renin completely disappears after binephrectomy. Residual putative reninlike activity, where investigated, has had the characteristics of lysosomal acid proteases. Occasional reports of renin or renin mRNA in vascular and cardiac tissues can be ascribed to failure to remove the kidneys 24 hours beforehand, overloading of detection systems, problems with stringency in identification, and illegitimate transcripts after more than 25 cycles of polymerase chain reaction. Others, using more stringent criteria, have failed to detect cardiac and vascular renin mRNA. Accordingly, a growing number of investigators have concluded that the kidneys are the only source of cardiovascular tissue renin. Although prorenin is secreted from extrarenal tissues as well as from the kidneys, there is no evidence that it is ever converted to renin in the circulation. The kidney is the only tissue with known capacity to convert prorenin to renin and to secrete active renin into the circulation. Accordingly, renin of renal origin determines plasma and hence, extracellular fluid renin levels. In these loci, angiotensin (Ang) I, formed by renin cleavage of circulating and interstitial fluid angiotensinogen, is in turn cleaved by angiotensin converting enzyme, located in plasma and extracellular fluids and on the luminal surface of pulmonary and systemic vascular endothelial cells, to Ang II, which perfuses and bathes the heart and vasculature. Consistent with this model, plasma renin and angiotensin and the antihypertensive action of renin inhibitors, converting enzyme inhibitor, or Ang II antagonists all disappear after binephrectomy. Thus, the plasma renin level, via Ang II formation, determines renin system vasoconstrictor activity, the antihypertensive potential of anti-renin system drugs, and the risk of heart attack in hypertensive patients. This analysis redirects renin research to renal mechanisms that create the plasma renin level, to renal prorenin biosynthesis and its processing to renin, and to their regulated secretion, extracellular distribution, and possible binding to by target tissues. In this context, it is still possible that changes in circulating and interstitial renin substrate or available converting enzyme might exert subtle modulating influences on Ang II formation. However, this analysis redefines the importance of plasma renin measurements to assess clinical situations, because plasma renin is the only known initiator driving the cardiovascular renin-angiotensin system, and its strength can be measured.

Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome

“…48 More recently described local RASes, which occur in virtually ever organ and tissue in which their presence has been evaluated, are classified as 'extrinsic' or 'intrinsic' depending on the origin of RAS system components. In extrinsic local RASes (RAS L [ext] ), such as is believed to occur in the heart, 49 one or more of the RAS components are synthesized locally but others are derived from the endocrine RAS. In intrinsic local RASes (RAS L [int] ), all of the components of a functional RAS are synthesized locally.…”

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy

“…Although it is still controversial whether active renin is derived directly from the kidney or synthesised locally in the heart or blood vessels, 40,41 all other major components of the RAS have been localised in the heart and blood vessels. Thus, both circulating and tissue angiotensins play important roles in cardiovascular homeostasis.…”

Biochemical properties of renin and prorenin binding to the (pro)renin receptor

“…This enzyme is secreted into the blood stream only from the juxtaglomerular cells of the kidney in response to cellular stimuli. 5,6 On the other hand, prorenin, the inactive precursor of renin, has been found to synthesize not only in the juxtaglomerular cells but also in many other tissues such as the collecting duct, adrenal, zona glomerulosa, eye, Müller cells, mast cells, ovary, thecal cells, uterus, myometrium/decidual cells, placenta, chorionic cells, testis and Leydig cells, and submandibular gland. 7 Prorenin is secreted from these tissues into the blood constitutively 5,6,8 and its level in the circulation is 10 times higher than that of mature renin.…”

“…5,6 On the other hand, prorenin, the inactive precursor of renin, has been found to synthesize not only in the juxtaglomerular cells but also in many other tissues such as the collecting duct, adrenal, zona glomerulosa, eye, Müller cells, mast cells, ovary, thecal cells, uterus, myometrium/decidual cells, placenta, chorionic cells, testis and Leydig cells, and submandibular gland. 7 Prorenin is secreted from these tissues into the blood constitutively 5,6,8 and its level in the circulation is 10 times higher than that of mature renin. 9,10 The precursor of renin is inactive, because the prosegment region with 43 amino acid residues covers the active site of renin with 339-341 residues.…”