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Ah Jan Danser - One of the best experts on this subject based on the ideXlab platform.
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Juxtaglomerular Cell Phenotypic Plasticity
High Blood Pressure & Cardiovascular Prevention, 2017Co-Authors: Alexandre Góes Martini, Ah Jan DanserAbstract:Renin is the first and rate-limiting step of the Renin-angiotensin system. The exclusive source of Renin in the circulation are the juxtaglomerular cells of the kidney, which line the afferent arterioles at the entrance of the glomeruli. Normally, Renin production by these cells suffices to maintain homeostasis. However, under chronic stimulation of Renin release, for instance during a low-salt diet or antihypertensive therapy, cells that previously expressed Renin during congenital life re-convert to a Renin-producing cell phenotype, a phenomenon which is known as “recruitment”. How exactly such differentiation occurs remains to be clarified. This review critically discusses the phenotypic plasticity of Renin cells, connecting them not only to the classical concept of blood pressure regulation, but also to more complex contexts such as development and growth processes, cell repair mechanisms and tissue regeneration.
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Abstract 161: The (Pro)Renin Receptor Regulates Renin Release and ProRenin-to-Renin Conversion in (Pro)Renin-Synthesizing Human Mast Cells
Hypertension, 2013Co-Authors: Manne Krop, Jeanette M.g. Van Gool, Ingrid M Garrelds, Ah Jan DanserAbstract:The (pro)Renin receptor ((P)RR), also known as ATP6AP2, is an accessory protein of the vacuolar H + -ATPase (V-ATPase), which is required for V-ATPase integrity and function. V-ATPases play an important role in acidifying intracellular compartments that are important for multiple cellular events such as proteolytic processing of proinsulin. To investigate whether the (P)RR affects proRenin-to-Renin conversion, we studied the consequences of (P)RR knockdown in (pro)Renin-synthesizing human mast cells (HMC-1). HMC-1 cells were transfected with siRNA against the (P)RR using Nucleofector ® kit L with Amaxa ® Nucleofector device, and the medium and cellular Renin/proRenin content were measured by immunoradiometric assay (Cisbio, France) after 48, 72 and 96 hours (four experiments in duplicate). (P)RR siRNA (but not mock transfection or negative control siRNA) decreased the (P)RR protein levels by up to 95% from 18-96 hours after transfection. Renin medium levels amounted to 9.61.6, 13.13.3 and 14.54.1 pg/mg protein at 48, 72 and 96 hours, whereas the concomitant proRenin levels were 19.64.1, 31.510.4 and 36.811.1 pg/mg protein. Cells exclusively contained Renin, and the Renin content at 48 hours (28131 pg/mg protein) was not different from that at 72 and 96 hours. Whereas negative control siRNA did not affect these levels, (P)RR siRNA increased Renin release at 72 and 96 hours 5-7-fold, and doubled the proRenin release at these time points. As a consequence, the % of total Renin (=Renin + proRenin) released by HMC-1 as Renin doubled. No siRNA effects were noted on the cellular Renin content. In conclusion, (P)RR knockdown affects both proRenin-Renin conversion and (pro)Renin release, resulting in a net rise of the Renin/proRenin ratio in the medium.
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The increase in Renin during Renin inhibition: does it result in harmful effects by the (pro)Renin receptor?
Hypertension Research, 2010Co-Authors: Ah Jan DanserAbstract:Renin inhibitors, similar to all Renin–angiotensin system (RAS) blockers, increase the plasma concentration of Renin because they attenuate the negative feedback effect of angiotensin (Ang) II on Renin release. The increase in Renin has been suggested to be higher than that during other types of RAS blockade. This could potentially limit the effectiveness of Renin inhibition, either because Ang II generation might occur again (‘Ang II escape’), possibly even at the levels above baseline, as has been described before for angiotensin-converting enzyme inhibitors, or because high levels of Renin will stimulate the recently discovered (pro)Renin receptor, and thus induce effects in an Ang-independent manner. This review shows first that the cause(s) of the Renin increase during treatment with the Renin inhibitor aliskiren is the consequence of a combination of factors, including an assay artifact, allowing the detection of proRenin as Renin, and a change in Renin half-life. When correcting for these phenomena the increase is unlikely to be as excessive as originally thought. The review then critically describes the consequence(s) of such a increase, concluding (i) that an Ang II escape is highly unlikely, given the [aliskiren]/[Renin] stoichiometry, and (ii) that Renin and proRenin downregulate their receptor (similar to many agonists). On the basis of the latter, one could even speculate that this will be more substantial when the Renin and proRenin levels are higher. Thus, from this point of view the larger increase in Renin during Renin inhibition will cause a stronger reduction in (pro)Renin receptor expression, and a greater suppression of (pro)Renin receptor-mediated effects than other Renin–Ang blockers.
A. H. Jan Danser - One of the best experts on this subject based on the ideXlab platform.
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Circulating versus tissue Renin-angiotensin system: On the origin of (pro)Renin
Current Hypertension Reports, 2008Co-Authors: Manne Krop, A. H. Jan DanserAbstract:Angiotensin synthesis at tissue sites is well established, and interference with tissue angiotensin is now believed to underlie the beneficial effects of Renin-angiotensin system blockers. Initially, it was thought that the Renin required to synthesize angiotensin at tissue sites was also synthesized locally. However, recent studies show this is not the case at important cardiovascular sites (eg, the heart and vessel wall). Moreover, extrarenal sites that express the Renin gene release proRenin, the inactive precursor of Renin, instead of Renin. This review provides an update on the sources of (pro)Renin in the body, lists the known stimulants and inhibitors of its production, and discusses the concept that proRenin rather than Renin determines tissue angiotensin generation.
Fumiaki Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Renin ANGIOTENSIN SYSTEM IN THE CONTEXT OF Renin, PRORenin, AND THE (PRO)Renin RECEPTOR
2013Co-Authors: Ahm Nurun Nabi, Tsutomu Nakagawa, Kazal Boron Biswas, Akio Ebihara, Fumiaki SuzukiAbstract:Since the discovery of Renin by Tigerstedt in 1898, the complex roles of the components of the Renin angiotensin system (RAS)have been extensively studied. RAS is involved in maintaining the homeostasis of body fluids and thus regulates the blood pressure.Renin is the key regulatory enzyme of RAS that catalyzes its only substrate angiotensinogen into the decapeptide angiotensin I,which is then converted into the octapeptide angiotensin II by angiotensin converting enzyme. Angiotensin II exerts its physiologicaleffects through angiotensin type 1 and type 2 receptors. Elucidation of the three-dimensional structure of Renin has led to the designand synthesis of several synthetic peptides that inhibit Renin activity, controlling blood pressure. Nephrectomized animals haveno detectable level of Renin in their blood plasma, indicating that the kidney is the only source of Renin. Renin is synthesized aspreproRenin, which is processed into proRenin. ProRenin is the preactive form of Renin, with an extra 43 amino acid residues that blockthe active site of Renin. ProRenin can be converted into Renin proteolytically by the action of trypsin, cathepsin, and other proteases.However, non-proteolytically activated proRenin (using acidic pH, low temperature, or protein-protein interactions) is also possible,resulting in enzymatically active Renin. The (pro)Renin receptor [(P)RR], a RAS member, activates proRenin through protein–proteininteractions and exhibits angiotensin II-dependent as well as angiotensin II-independent functions. (P)RR in conjunction with (pro)Reninexerts pathophysiological activities in human and animal models, especially in end-stage organ damage. Design of peptides that mimicparts of Renin/proRenin can help to explain the binding interaction between (P)RR and its ligands. This article includes a discussion ofthe complex current challenges of studying Renin, proRenin, and (P)RR.
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Aliskiren binds to Renin and proRenin bound to (pro)Renin receptor in vitro.
Hypertension Research, 2010Co-Authors: Kazal Boron Biswas, Tadashi Inagami, Tsutomu Nakagawa, Atsuhiro Ichihara, Ahm Nurun Nabi, Yoshie Arai, Akio Ebihara, Toshifumi Watanabe, Fumiaki SuzukiAbstract:Human (pro)Renin receptor ((P)RR) has been implicated in the augmentation of many biological and cellular processes through bindings to its ligands, Renin and proRenin. In this study, we investigated the effects of aliskiren, a direct oral Renin inhibitor, on the activities of free and (P)RR-bound forms of human mature Renin. We also elucidated the effect of aliskiren on the 'Renin activity' of the receptor-bound form of proRenin. Aliskiren had an IC(50) of 0.72 nmol l(-1) against Renin. The compound competitively inhibited Renin activity with an inhibitory constant (K(i)) of 0.18 nmol l(-1). Furthermore, the dissociation constants (K(D)) for aliskiren from Renin and proRenin bound to (P)RR were determined using surface plasmon resonance in a BIAcore assay system (Uppsala, Sweden). These values were estimated to be 0.46 ± 0.03 and 0.25 ± 0.01 nmol l(-1), respectively. The compound competitively inhibited the Renin activities of (P)RR-bound forms of both Renin and proRenin with a K(i) of 0.14 and 0.15 nmol l(-1), respectively. These results indicate that aliskiren could be a potent inhibitor of the free forms of mature Renin and of the receptor-bound forms of Renin and proRenin.
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Biochemical properties of Renin and proRenin binding to the (pro)Renin receptor
Hypertension Research, 2010Co-Authors: Ahm Nurun Nabi, Fumiaki SuzukiAbstract:The discovery of (pro)Renin receptor, (P)RR, has made the Renin–angiotensin system (RAS) more multifaceted. Interaction of Renin and proRenin with this receptor has set a new perspective about the physiological functions, activation mechanism and pathophysiological roles of Renin/proRenin. Uses of peptides mimicking the structure of the ligands have been very effective for determining structure–function relationship between the ligands and receptor. The probable pivotal role of decoy peptide region (R^10PIFLKRMPSI^19P) of proRenin prosegment was suggested for higher binding affinity of proRenin to (P)RR than that of mature Renin. Recently, ‘hinge’ region peptide (S^149QGVLKEDVF^158) in Renin/proRenin molecule has been reported. BothRenin and proRenin can interact with (P)RR through the ‘hinge’ region. Furthermore, it has been proposed that proRenin has multiple binding sites whereas Renin has a single binding site for (P)RR. To comprehend the activation mechanism of Renin and proRenin after receptor binding, it is very important to understand their interaction with the receptor. Several kinds of peptides designed from the regions of the tertiary structure of Renin and predicted model of proRenin facilitated the study of the in vitro binding mechanisms for Renin and proRenin to (P)RR. Here, a series of recent in vitro studies was reviewed to discuss a possible binding mechanism of Renin/proRenin to the (P)RR.
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Ser84 of Human Renin Contributes to the Biphasic pH Dependence of the Renin-Angiotensinogen Reaction
Bioscience Biotechnology and Biochemistry, 2007Co-Authors: Hideyuki Iwata, Tsutomu Nakagawa, Kazuhiro Nishiuchi, Tomoaki Hiratsuka, Ryousuke Satou, Yuichiro Yoshioka, Youko Fukui, Fumiaki Suzuki, Yukio NakamuraAbstract:The pH dependence of the reaction of various Renins was investigated using sheep angiotensinogen as a substrate. Human Renin showed two separate peaks, but rat and mouse Ren1 Renins showed one peak with a shoulder. A comparison of the predicted subsite residues of human Renin with those of rat and mouse Ren1 Renins revealed that Arg82, Ser84, Thr85, Ala229, and Thr312 are unique in the human sequence. We examined the possible importance of these residues in the unique pH profile of the human Renin reaction by replacing these residues with the corresponding residues of rat Renin. The replacement of Ser84 of human Renin with Gly changed the pH dependence of the reaction to one peak, similarly to rat and mouse Ren1 Renins. Other mutant human Renins kept two separate peaks, similarly to wild-type human Renin. These results indicate that Ser84 of human Renin contributes to the biphasic pH dependence of the Renin-angiotensinogen reaction.
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Renin-angiotensin system
Nihon rinsho. Japanese journal of clinical medicine, 1992Co-Authors: Fumiaki SuzukiAbstract:Renin is a key enzyme in the Renin-angiotensin system (RAS) which controls the blood pressure and electrolyte balance. By numerous studies on RAS and structures of Renin and proRenin, the determination of three-dimensional structure for Renin has been thought to be important in the rational approach to the drug design for antihypertensives. Here, several investigations for the three-dimensional structure of human and mouse Renins are reviewed. These papers showed that the active site cleft had a less open arrangement in Renins than that in other aspartic proteinases, although the general topology of both Renins were quite similar. They also described subsites of Renins and others.
Stephen A. Katz - One of the best experts on this subject based on the ideXlab platform.
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Active Renin and Renin glycoform dynamics in the carotid artery.
American Journal of Physiology-heart and Circulatory Physiology, 1996Co-Authors: Stephen A. Katz, John A. Opsahl, Lynn M. Forbis, Woubeshet AyenewAbstract:Active Renin and five major active Renin glycoforms were measured in plasma and the carotid wall of anesthetized rabbits before and after 1.5- and 24-h bilateral nephrectomy (BNX). Before BNX, there was no difference in Renin glycoform proportions between plasma and the carotid wall. Plasma Renin concentration (PRC) fell by 67% after 1.5-h BNX due to preferential clearance of Renin glycoforms I+II, but no significant change in Renin concentration was seen in the carotid artery (or aorta). Twenty-four hours after BNX, PRC and carotid wall Renin concentrations were reduced by 99.7 and 97.7%, respectively, while the proportion of Renin glycoforms I+II in the carotid wall was significantly elevated. These data are consistent with the view that vascular Renin is derived from plasma Renin of renal origin. After BNX, Renin disappearance from the carotid (and aortic wall) is slower than Renin decay from plasma, and the less negatively charged active Renin glycoforms I+II exit the carotid wall much more slowly than the more negatively charged glycoforms. After 24-h BNX, Renin glycoforms I+II were still effluxing from the vascular wall and represented the only glycoforms present in the carotid wall.
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The relationship between Renin isoelectric forms and Renin glycoforms
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 1994Co-Authors: Stephen A. Katz, John A. Opsahl, Paul A. Abraham, M. J. GardnerAbstract:Active Renin can be separated into multiple isoelectric forms using shallow gradient isoelectric focusing and into multiple glycoforms using concanavalin A (Con A) affinity chromatography. The relationship between Renin isoelectric forms and glycoforms has not been previously determined. In this study, each of three Renin Con A glycoforms from rat kidney was composed of significantly different proportions of six Renin isoelectric forms; glycoforms with the greatest affinity for Con A contained proportionally less of the acidic isoelectric forms than those with the least affinity for Con A. A set of compartmental models accurately predicted previously measured differential plasma clearance rates of the three Renin glycoforms based on their corresponding isoelectric form proportions. We conclude that 1) each Con A Renin glycoform is composed of significantly different proportions of isoelectric forms, and 2) the different proportions of isoelectric forms found in Con A glycoforms are sufficient to account for the differential Renin plasma clearance rates demonstrated previously for Renin glycoforms in the rat. These data suggest that the isoelectric and glycoform heterogeneity of active Renin are, in fact, closely related and may result from variable and interrelated mannose (Con A affinity) and sialic acid (charge) attachments to Renin.
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The Renin-angiotensin system in the type II diabetic obese Zucker rat.
Journal of The American Society of Nephrology, 1993Co-Authors: Christian T. Harker, Michael P. O'donnell, Bertram L. Kasiske, William F. Keane, Stephen A. KatzAbstract:: Recently, the obese Zucker rat (OZR), an animal model of non-insulin-dependent (type II) diabetes, was shown to respond to converting enzyme inhibition with decreased albuminuria and a marked attenuation of glomerular injury. It was hypothesized that the OZR would possess low plasma Renin values and an increased vascular responsiveness to angiotensin II, and therefore, the Renin-angiotensin system (PRA, active Renin, inactive Renin, renal Renin content, and plasma angiotensinogen) and vascular reactivity in OZR at 10 and 24 wk of age were investigated. PRA and Renin concentration, inactive plasma Renin, and renal Renin content were all significantly (P < 0.05) reduced in OZR when compared with age-matched lean controls. The ratio of inactive to total Renin was significantly increased in the OZR. OZR aortic ring vascular reactivity to KCl, norepinephrine, and angiotensin II was assessed. Despite essentially equal or increased contractile responses to KCl and norepinephrine at both 10 and 24 wk of age, the OZR was not more sensitive to angiotensin II and displayed a significantly reduced contractile response to angiotensin II at 24 wk of age, when compared with lean age-matched controls. It was concluded that the renal protective effect of converting enzyme inhibition in OZR, despite significantly reduced PRA and concentration, inactive plasma Renin, and renal Renin content, may not be due to a diabetes-induced increased vascular reactivity to angiotensin II.
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Role of Renin isoelectric heterogeneity in renal storage and secretion of Renin.
Journal of The American Society of Nephrology, 1993Co-Authors: John A. Opsahl, Paul A. Abraham, Jay G. Shake, Stephen A. KatzAbstract: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.
Manne Krop - One of the best experts on this subject based on the ideXlab platform.
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Abstract 161: The (Pro)Renin Receptor Regulates Renin Release and ProRenin-to-Renin Conversion in (Pro)Renin-Synthesizing Human Mast Cells
Hypertension, 2013Co-Authors: Manne Krop, Jeanette M.g. Van Gool, Ingrid M Garrelds, Ah Jan DanserAbstract:The (pro)Renin receptor ((P)RR), also known as ATP6AP2, is an accessory protein of the vacuolar H + -ATPase (V-ATPase), which is required for V-ATPase integrity and function. V-ATPases play an important role in acidifying intracellular compartments that are important for multiple cellular events such as proteolytic processing of proinsulin. To investigate whether the (P)RR affects proRenin-to-Renin conversion, we studied the consequences of (P)RR knockdown in (pro)Renin-synthesizing human mast cells (HMC-1). HMC-1 cells were transfected with siRNA against the (P)RR using Nucleofector ® kit L with Amaxa ® Nucleofector device, and the medium and cellular Renin/proRenin content were measured by immunoradiometric assay (Cisbio, France) after 48, 72 and 96 hours (four experiments in duplicate). (P)RR siRNA (but not mock transfection or negative control siRNA) decreased the (P)RR protein levels by up to 95% from 18-96 hours after transfection. Renin medium levels amounted to 9.61.6, 13.13.3 and 14.54.1 pg/mg protein at 48, 72 and 96 hours, whereas the concomitant proRenin levels were 19.64.1, 31.510.4 and 36.811.1 pg/mg protein. Cells exclusively contained Renin, and the Renin content at 48 hours (28131 pg/mg protein) was not different from that at 72 and 96 hours. Whereas negative control siRNA did not affect these levels, (P)RR siRNA increased Renin release at 72 and 96 hours 5-7-fold, and doubled the proRenin release at these time points. As a consequence, the % of total Renin (=Renin + proRenin) released by HMC-1 as Renin doubled. No siRNA effects were noted on the cellular Renin content. In conclusion, (P)RR knockdown affects both proRenin-Renin conversion and (pro)Renin release, resulting in a net rise of the Renin/proRenin ratio in the medium.
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Circulating versus tissue Renin-angiotensin system: On the origin of (pro)Renin
Current Hypertension Reports, 2008Co-Authors: Manne Krop, A. H. Jan DanserAbstract:Angiotensin synthesis at tissue sites is well established, and interference with tissue angiotensin is now believed to underlie the beneficial effects of Renin-angiotensin system blockers. Initially, it was thought that the Renin required to synthesize angiotensin at tissue sites was also synthesized locally. However, recent studies show this is not the case at important cardiovascular sites (eg, the heart and vessel wall). Moreover, extrarenal sites that express the Renin gene release proRenin, the inactive precursor of Renin, instead of Renin. This review provides an update on the sources of (pro)Renin in the body, lists the known stimulants and inhibitors of its production, and discusses the concept that proRenin rather than Renin determines tissue angiotensin generation.
