Renal secretion and hepatic clearance of human multiple renin forms.
TL;DR: The preferential secretion and clearance of the more basic forms of renin may contribute to short-term control of human renin-angiotensin system activity.
Abstract: Human active renin can be separated into at least five forms by isoelectric focusing. The present study assessed the preferential renal secretion and hepatic degradation of renin forms in humans. The renin form profile of secreted renal renin was determined before transplant in an ex vivo kidney donor perfusion system and compared with the peripheral plasma multiple renin form profile of normal subjects. The effect of hepatic degradation on renin forms was assessed in hepatic vein plasma in comparison with infrarenal vena cava plasma in hypertensive patients during renal vein renin studies. The results revealed a significantly greater proportion of the more basic forms in the perfusate of donor kidneys compared with normal plasma. In hypertensive patients the proportion of the more basic renin forms in the hepatic vein was significantly decreased in comparison with the infrarenal vena cava. Thus, the human kidney may preferentially secrete the more basic renin forms. In contrast, the liver preferentially degrades the more basic forms, giving these forms a shorter plasma half-life. The preferential secretion and clearance of the more basic forms of renin may contribute to short-term control of human renin-angiotensin system activity.
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TL;DR: The existence of a local renin-angiotensin system in the heart is still a controversial issue and the role of alternative angiotENSin-generating enzymes (cathepsin, chymase) and the possibility of (pro)renin uptake from the circulation is evaluated.
Abstract: The existence of a local renin-angiotensin system in the heart is still a controversial issue. This review discusses the evidence, obtained from studies in cardiac cells, in isolated perfused hearts and in intact animals and humans, both under normal and pathological conditions, for local production of prorenin, renin, angiotensinogen, angiotensin-converting enzyme, angiotensin I and angiotensin II at cardiac tissue sites. In addition, the role of alternative angiotensin-generating enzymes (cathepsin, chymase) and the possibility of (pro)renin uptake from the circulation is evaluated.
88 citations
TL;DR: It is concluded that in control rats, active renin andactive renin glycoforms are distributed as if in diffusion equilibrium between plasma and the myocardial interstitial space, and most cardiac renin is derived from plasma renin of renal origin.
Abstract: In an attempt to clarify the relationship of the circulating and myocardial renin-angiotensin systems, active renin concentration, its constituent major glycoforms (active renin glycoforms I through V), and angiotensinogen were measured in plasma and left ventricular homogenates from sodium-depleted rats under control conditions or 2 minutes, 3 hours, 6 hours, and 48 hours after bilateral nephrectomy (BNX). Control myocardial renin concentration was 1.4±0.1 ng angiotensin I (Ang I) per gram myocardium per hour and plasma renin concentration was 6.7±1.1 ng Ang I per milliliter plasma per hour. Control myocardial angiotensinogen was 0.042±0.004 μmol/kg myocardium and plasma angiotensinogen was 1.5 μmol/L plasma. Two minutes after BNX and corresponding stimulation of renin secretion by anesthesia and surgery, plasma renin concentration was increased disproportionately compared with myocardial renin. Three, 6, and 48 hours after BNX, renin decay occurred significantly faster from the plasma than from the myocardium. Forty-eight hours after BNX, myocardial renin concentrations had fallen to 15% of control values, while myocardial angiotensinogen concentrations had increased 12-fold and plasma angiotensinogen concentrations had increased by only 3.5-fold. Myocardial renin glycoform proportions were identical in myocardial homogenates and plasma in control animals. At 6 hours BNX, the proportions of plasma active renin glycoforms I+II fell, while those in the myocardium significantly increased. We conclude that in control rats, active renin and active renin glycoforms are distributed as if in diffusion equilibrium between plasma and the myocardial interstitial space. After BNX, myocardial renin concentration falls dramatically, suggesting that most cardiac renin is derived from plasma renin of renal origin. After BNX, renin glycoforms I+II are preferentially cleared from the plasma but preferentially retained by the myocardium. Control myocardial angiotensinogen concentrations are too low to result from simple diffusion equilibrium between plasma and the myocardial interstitium.
88 citations
TL;DR: The ways in which the renin-angiotensin system maintains normal cardiovascular homeostasis during development and its participation in physiologic and biochemical events are reviewed.
22 citations
TL;DR: Both acute and acute on chronic stimulation of renal renin secretion increased circulating ARC and shifted the profile of circulating renin toward the less negatively charged forms but did not change inactive renin concentrations.
10 citations
TL;DR: This study suggests that the disproportionate increase in circulating basic forms of renin observed after acute stimulation reflects the net effect of preferential renal the more basic renin isoelectric forms, which results in an overall circulating renin activity with a shorter half-life.
Abstract: Renin is a glycoprotein that is heterogeneous with respect to carbohydrate content and net charge. In an attempt to clarify the role of renin isoelectric heterogeneity in renal renin storage and secretion, the isoelectric profile of renal renin, secreted renin, and circulating renin were directly assessed and compared under basal and stimulated conditions by the use of an in vivo blood perfused rabbit kidney preparation. Under basal conditions, the kidney preferentially stored and secreted the relatively basic isoelectric forms of renin. Acute stimulation of renin secretion (reduced renal perfusion pressure and angiotensin-converting enzyme inhibition) significantly increased the secretion of the relatively basic isoelectric forms but had very little effect on the secretion of the relatively acidic renin forms. Circulating renin was composed primarily of relatively basic forms, which increased disproportionately after stimulation of renin secretion. These findings suggest that the isoelectric heterogeneity of renin is important in the cellular processing of renin and can be explained by a two-pool model in which the relatively acidic isoelectric forms of renin are constitutively secreted (and not stored) and the relatively basic isoelectric forms represent a regulated pathway in which they are stored and rapidly released in response to acute secretory stimuli. Preferential hepatic extraction of the more basic isoelectric forms has previously been described. Data from this study suggest that the disproportionate increase in circulating basic forms of renin observed after acute stimulation reflects the net effect of preferential renal the more basic renin isoelectric forms. The disproportionate increase in relatively basic circulating renin forms after acute secretory stimulation results in an overall circulating renin activity with a shorter half-life.
10 citations
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TL;DR: Renin activity increased with Na restriction, was significantly higher on upright activity during both normal and restricted Na intake, and was most markedly elevated following the diuretic.
Abstract: A radioimmunoassay for angiotensin I and its application to the determination of renin activity is described. The assay employs antibodies raised to copolymers of angiotensin I and succinylated poly-l-lysine. Angiotensin labeled with 125I and purified by high voltage paper electrophoresis is employed as a tracer. Incubation is carried out in plasma in the presence of 3 metal binding reagents which serve to inhibit effectively proteolytic attack on angiotensin I. Immunoassay of generated angiotensin I is carried out directly on plasma diluted 1:20. Fifteen normal volunteers were studied on a metabolic ward at 2 levels of Na intake, during recumbency and upright posture, and following the administration of furosemide. Renin activity increased with Na restriction, was significantly higher on upright activity during both normal and restricted Na intake, and was most markedly elevated following the diuretic. Renin values obtained by immunoassay of angiotensin I correspond closely to those observed by ...
2,348 citations
TL;DR: Human renin was purified from a juxtaglomerular cell tumor with a high renin content and antibody raised against tumor renin completely inhibited the activity of both tumor and standard renin.
123 citations
TL;DR: Renin was found to be a glycoprotein containing glucosamine and possessing binding affinity to concanavalin A that has a broad pH optimum between pH 5.5 and 7.0 for both hog angiotensinogen and the synthetic octapeptide substrate benzyloxycarbonyl-Pro-Phe-His-Leu- Leu-Val-Tyr-Ser-beta-naphthylamide.
112 citations
TL;DR: Human renin was expressed from cloned DNA in Xenopus oocytes and a mouse L cell line and its biosynthesis and posttranslational modifications were characterized to demonstrate that renin is recognized by the phosphotransferase and suggest that ren in contains at least part of the lysosomal protein recognition domain.
Abstract: Renin is an aspartyl protease which is highly homologous to the lysosomal aspartyl protease cathepsin D. During its biosynthesis, cathepsin D acquires phosphomannosyl residues that enable it to bind to the mannose 6-phosphate (Man-6-P) receptor and to be targeted to lysosomes. The phosphorylation of lysosomal enzymes by UDP-GlcNAc:lysosomal enzyme N-acetylglucosaminylphosphotransferase (phosphotransferase) occurs by recognition of a protein domain that is thought to be present only on lysosomal enzymes. In order to determine whether renin, being structurally similar to cathepsin D, also acquires phosphomannosyl residues, human renin was expressed from cloned DNA in Xenopus oocytes and a mouse L cell line and its biosynthesis and posttranslational modifications were characterized. In Xenopus oocytes, the majority of the renin remained intracellular and underwent a proteolytic cleavage which removed the propiece. Most of the renin synthesized by oocytes was able to bind to a Man-6-P receptor affinity column (53%, 57%, and 90%, in different experiments), indicating the presence of phosphomannosyl residues. In the L cells, the majority of the renin was secreted but 5-6% of the renin molecules contained phosphomannosyl residues as demonstrated by binding of [35S]methionine-labeled renin to the Man-6-P receptor as well as direct analysis of [2-3H]mannose-labeled oligosaccharides. Although the level of renin phosphorylation differed greatly between the two cell types examined, these results demonstrate that renin is recognized by the phosphotransferase and suggest that renin contains at least part of the lysosomal protein recognition domain.
79 citations
TL;DR: Rin synthesis and secretion is complex and may be subject to regulation at multiple steps, and it is proposed that renin can be secreted by two different pathways.
Abstract: Processing of renin involves sequential proteolytic cleavages of a preproform to the active mature forms. Preprorenin is rapidly internalized cotranslationally into the rough endoplasmic reticulum and hydrolyzed by signal peptidase to produce prorenin. In the Golgi, prorenin is converted (within 15 min) to a form of renin that is enzymatically active. Over the next 12 hr, a slow intracellular process removes a dipeptide near the carboxyl terminus, converting the one-chain renin into two chains joined by a single disulfide bond. This conversion occurs during formation, condensation, and packaging of renin granules. The resultant two-chain renin is approximately one-sixth as active as the one-chain form. The intact renin molecule is obligatory for enzymatic activity because heavy chain alone has little or no activity. Both one- and two-chain renins are secreted, but prorenin is not. Multiple isoelectric forms of prorenin, one-chain renin, and two-chain renin are also observed. This microheterogeneity probably results from minor differences in amino acid composition as a consequence of variations in cleavage positions during processing. Thus, these data suggest that renin synthesis and secretion is complex and may be subject to regulation at multiple steps. Furthermore, based on the results of this study, we also propose that renin can be secreted by two different pathways.
65 citations