Aliskiren Accumulates in Renin Secretory Granules and Binds Plasma Prorenin

Krop, Manne; Garrelds, Ingrid M.; Bruin, René J.A. de; Gool, Jeanette M.G. van; Fisher, Naomi D.L.; Hollenberg, Norman K.; Danser, A.H. Jan

doi:10.1161/hypertensionaha.108.123042

Cited by 82 publications

(74 citation statements)

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“…[57][58][59] Also, aliskiren bound to the active form of prorenin in vivo. 60,61 On the other hand, this renin inhibitor did not blunt bindings of renin and prorenin to (P)RR, whereas it significantly decreased the mRNA expression of (P)RR in the kidney cortex of diabetic hypertensive Ren2 rats. 61 A peptide like renin inhibitor was first reported by Szelke et al 62 Peptides derived from the bovine pepsinogen (17 residues at the NH 2 -terminus of bovine and 1-16 residues of the porcine pepsinogens) were found to inhibit pepsin activity in a milk clotting assay at pH 5.5 with high values of K i .…”

Section: Effects Of Aliskiren Hrp/decoy and 'Hinge' Peptides On Renimentioning

confidence: 82%

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

Nabi

Suzuki

2009

Hypertens Res

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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 10P IFLKRMPSI 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 149 QGVLKEDVF 158 ) in renin/prorenin molecule has been reported. Both renin 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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Section: Effects Of Aliskiren Hrp/decoy and 'Hinge' Peptides On Renimentioning

confidence: 82%

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

Nabi

Suzuki

2009

Hypertens Res

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“…The renin activity in this (pro)renin-aliskiren complex would be inhibited: this renin (or prorenin, which may undergo activation at tissue sites) could not cleave Aogen, and the tissue and systemic RAAS cascades would not be activated. As this mechanism should operate independently of plasma drug levels, 101 it may help to explain the prolonged BP benefits observed in rats discussed earlier, and in patients in whom aliskiren treatment has been stopped. 104 Aliskiren, prorenin and the (pro)renin receptor The recent discovery of a receptor for renin and prorenin, the (P)RR, 105 has added an important new dimension to the tissue RAAS.…”

Section: Aliskiren Localizes In the Kidneymentioning

confidence: 88%

“…However, a human mast cell line synthesizes and secretes (pro)renin. 100 Krop and coworkers 101 used these cells to ask whether aliskiren can incorporate into renin granules. They found that mast cells that had been incubated for 7 days with aliskiren secreted renin that displayed inhibited enzyme activity (that is, inhibited Ang I-forming capacity).…”

Section: Aliskiren Localizes In the Kidneymentioning

confidence: 99%

“…Inhibition of Ang II formation on cell surface (116) Persistent tissue RAAS blockade (91) Long renal residence time (90) • Decreased (P)RR synthesis • No activation of prorenin when it binds to (P)RR (116) • No gain in catalytic activity when renin binds to (P)RR Renal protection (71,72,75,86,87,88) Incorporates into renin granules (101) (Pro)renin secreted as inhibited enzyme (101) Efficient renin inhibition (101) No chance to cleave Aogen Inhibition of Ang II formation (71) In tissue & plasma Glomerular localization (87) Inhibition of mesangial, podocyte (25) RAAS JG cells ( * ) Figure 3 In this working model of the renoprotective actions of aliskiren, outcomes for which in vitro or in vivo evidence exists are referenced (see References); no reference indicates a logical, but still speculative outcome. Solid arrows indicate the existence of in vitro or in vivo evidence to support a causal link between the events.…”

Section: Aliskiren Partitions To the Kidneymentioning

confidence: 99%

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New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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“…The detection limit of the EKA is 0.05 ng Ang I/ml per hour. Ang I-generating activities were converted to renin concentrations based on the fact that 1 ng Ang I/ml per hour corresponds with 2.6 pg human renin/ml (15). Before their application in the IRMA, the urine samples from the patients with hypertension and diabetes were concentrated 5-fold with Amicon Ultra-10 centrifugal filter devices (EMD Millipore, Cork, Ireland).…”

Section: Biochemical Measurementsmentioning

confidence: 99%

Methodologic Issues in the Measurement of Urinary Renin

Roksnoer

Verdonk

Garrelds

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Alge et al. recently reported that urinary renin may be a prognostic biomarker for AKI after cardiac surgery. However, their urinary renin levels far exceeded published plasma renin levels, whereas normally, urinary renin is ,10% of plasma renin. This result raises questions about the specificity of the new Quantikine Renin ELISA Kit used in the work by Alge et al., which is claimed to detect total renin (i.e., renin and prorenin). Therefore, this study tested this assay.Design, setting, participants, & measurements Plasma and urine from 30 patients with hypertension, diabetes, or preeclampsia and 10 healthy pregnant women (randomly selected from sample sets obtained earlier to investigate urinary renin-angiotensin system components) were used to compare the ELISA with a validated renin immunoradiometric assay and an in-house enzyme kinetic assay. Measurements were performed before and after in vitro prorenin activation, representing renin and total renin, respectively.Results Total renin measurements by ELISA, immunoradiometric assay, and enzyme kinetic assay were highly correlated. However, ELISA results were consistently $10-fold higher. The ELISA standard yielded low to undetectable levels in the immunoradiometric assay and enzyme kinetic assay, except after prorenin activation, when the results were $10-fold lower than the ELISA results. In plasma, prorenin activation increased ELISA results by 10%-15%. Urine contained no detectable prorenin. ConclusionsThe ELISA renin kit standard is prorenin, and its immunoreactivity and enzymatic activity after conversion to renin do not match the International Reference Preparation of human renin that has been used to validate previous immunoradiometric assays and enzyme kinetic assays; in fact, they are at least 10-fold lower, and thus, any measurements obtained with this ELISA kit yield levels that are at least 10-fold too high. The ELISA antibodies detect both renin and prorenin, with a preference for the former. Given these inconsistencies, urinary renin levels should be measured by established renin assays.

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Aliskiren Accumulates in Renin Secretory Granules and Binds Plasma Prorenin

Cited by 82 publications

References 29 publications

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

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

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Methodologic Issues in the Measurement of Urinary Renin

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