Renal and Hormonal Responses to Direct Renin Inhibition With Aliskiren in Healthy Humans

Fisher, Naomi D.L.; Danser, A.H. Jan; Nussberger, Juerg; Dole, William P.; Hollenberg, Norman K.

doi:10.1161/circulationaha.108.767202

Cited by 151 publications

(130 citation statements)

References 46 publications

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“…As we studied patients under these conditions of high dietary sodium, the magnitude of our results may be less than would be expected under conditions of salt depletion, when the RAAS is activated and the response to RAAS blockers is enhanced [45]. The effect of sodium intake may be of particular importance in light of recent clinical trial data from the Reduction in End points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial (IDNT) that demonstrated enhanced renal protective effects of RAAS inhibition in participants with the two lowest tertiles of dietary sodium intake [20].…”

Section: Discussionmentioning

confidence: 64%

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

et al. 2013

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Aims/hypothesis Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy. Methods Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/ chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n=27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days. Results Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188±0.007 to 0.206±0.007, p=0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p<0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p=0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p<0.005). Conclusions/interpretation The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

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Section: Discussionmentioning

confidence: 64%

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

et al. 2013

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“…5 Such high concentrations do not occur in vivo during aliskiren treatment. 16 Nevertheless, even if only a small percentage of prorenin obtains the open conformation in vivo during aliskiren treatment, this may already result in an overestimation of the renin rise during renin inhibition. 4,7,8 Our current data show that ex vivo exposure of plasma samples obtained from aliskiren-treated subjects to 10 μmol/L aliskiren still led to further rises in immunoreactive renin.…”

Section: Discussionmentioning

confidence: 99%

New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold Prorenin

Krop

Lu²,

Verdonk³

et al. 2013

Hypertension

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R enin belongs to the A1 family of aspartic proteases. Its 3-dimensional (3D) structure consists of 2 β-sheet domains (N and C domain) related by an ≈2-fold axis. The active site is a deep cleft between the N and C domains that extends over 8 residues of renin's substrate, angiotensinogen. Each domain supplies 1 catalytic aspartic acid residue in the center of the binding cleft. A long β-hairpin loop structure called the flap in the N-terminal domain covers the central part of the angiotensinogen-binding site, and the conformation with the tip of the flap open allows the entrance of the substrate and removal of hydrolytic products during the catalytic turnover, while the tip closes on substrate binding. 1 In the case of renin's inactive precursor, prorenin, the flap is open to accommodate the 43-amino acid prosegment.1,2 Morales et al 2 recently proposed that in prorenin, the catalytic binding site is covered by the N-terminal part of mature renin that, in turn, is covered by the prosegment. After removal of the prosegment, this N-terminal part becomes part of a 6-stranded β-sheet on the back of the mature renin molecule, previously occupied by the prosegment. This requires a conformational change that fully exposes the active cleft. 2Prosegment unfolding occurs in a pH-and temperaturedependent manner and, if not followed by cleavage, results in 2 prorenin conformations as follows: a closed, inactive form, and an open form that displays full enzymatic activity (Figure 1). 3,4 In addition, an intermediate form exists where the prosegment has moved away from the cleft, but where the renin part still has to undergo the above-mentioned conformational changes. Under physiological conditions, <2% of prorenin is in the open conformation. The recently introduced renin inhibitor, aliskiren ( Figure S1A in the online-only Data Supplement), binds to prorenin in the open conformation, as well as to the intermediate form of prorenin. 3,4 Binding to the intermediate form induces prorenin unfolding. Because of the tight binding of the renin inhibitor, the refolding step (ie, the return to the closed conformation) is no longer possible, and thus the equilibrium between the closed and open conformation will shift in favor of the open conformation. Eventually, depending on the concentration of aliskiren, a significant proportion of prorenin may be open (nonproteolytic activation), allowing its recognition by the active site-directed antibodies used in renin immunoradiometric assays (IRMAs), despite the fact that the Abstract-Renin inhibitors like aliskiren not only block renin but also bind prorenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a renin-specific assay. Consequently, aliskiren can be used to measure prorenin. VTP-27999 is a new renin inhibitor with an aliskiren-like IC 50 and t 1/2 , and a much higher bioavailability. This study addressed (pro)renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased renin immunoreactivi...

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“…19 Each subsequent aliskiren dose was given 2 days after the previous dose. Written informed consent was obtained from each patient, and the protocol was approved by the human subjects committee of the Brigham and Women's Hospital and Harvard Medical School.…”

Section: Human Studiesmentioning

confidence: 99%

Aliskiren Accumulates in Renin Secretory Granules and Binds Plasma Prorenin

et al. 2008

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Abstract-The vascular effects of aliskiren last longer than expected based on its half life, and this renin inhibitor has been reported to cause a greater renin rise than other renin-angiotensin system blockers. To investigate whether aliskiren accumulation in secretory granules contributes to these phenomena, renin-synthesizing mast cells were incubated with aliskiren, washed, and exposed to forskolin in medium without aliskiren (0.1 to 1000 nmol/L). (Pro)renin concentrations were measured by renin-and prorenin-specific immunoradiometric assays, and renin activity was measured by enzyme-kinetic assay. Without aliskiren, the culture medium predominantly contained prorenin, the cells exclusively stored renin, and forskolin doubled renin release. Aliskiren dose-dependently bound to (pro)renin in the medium and cell lysates and did not alter the effect of forskolin. The aliskiren concentrations required to bind prorenin were 1 to 2 orders of magnitude higher than those needed to bind renin. Blockade of cell lysate renin activity ranged from 27Ϯ15% to 79Ϯ5%, and these percentages were identical for the renin that was released by forskolin, indicating that they represented the same renin pool, ie, the renin storage granules. Comparison of renin and prorenin measurements in blood samples obtained from human volunteers treated with aliskiren, both before and after prorenin activation, revealed that Յ30% of prorenin was detected in renin-specific assays. In conclusion, aliskiren accumulates in renin granules, thus allowing long-lasting renin-angiotensin system blockade beyond the half-life of this drug. Aliskiren also binds to prorenin. This allows its detection as renin, and might explain, in part, the renin rise during renin inhibition. (Hypertension. 2008;52:1076-1083.)

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Renal and Hormonal Responses to Direct Renin Inhibition With Aliskiren in Healthy Humans

Cited by 151 publications

References 46 publications

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold Prorenin

Aliskiren Accumulates in Renin Secretory Granules and Binds Plasma Prorenin

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