Plasma pro-endothelin-1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism

Neeraj Dhaun, Jale Yuzugulen, Robert A Kimmitt, Elizabeth G Wood, Pajaree Chariyavilaskul, Iain M MacIntyre, Jane Goddard, David J Webb, Roger Corder, Neeraj Dhaun, Jale Yuzugulen, Robert A Kimmitt, Elizabeth G Wood, Pajaree Chariyavilaskul, Iain M MacIntyre, Jane Goddard, David J Webb, Roger Corder

Abstract

Background: Endothelin 1 (ET-1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET-1 peptides, endothelin-like domain peptide (ELDP) and C-terminal pro-ET-1 (CT-proET-1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists.

Methods and results: We assessed plasma and urine ELDP and plasma CT-proET-1 in CKD patients with minimal comorbidity. Next, in a randomized double-blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT-proET-1 increased with CKD stage (both P<0.0001), correlating inversely with estimated glomerular filtration rate (both P<0.0001). Following intervention, placebo and nifedipine did not affect plasma and urine ELDP or plasma CT-proET-1. Sitaxentan increased both plasma ELDP and CT-proET-1 (baseline versus week 6±SEM: ELDP, 11.8±0.5 versus 13.4±0.6 fmol/mL; CT-proET-1, 20.5±1.2 versus 23.3±1.5 fmol/mL; both P<0.0001). Plasma ET-1 was unaffected by any treatment. Following sitaxentan, plasma ELDP and CT-proET-1 correlated negatively with 24-hour urinary sodium excretion.

Conclusions: ELDP and CT-proET-1 increase in CKD and thus are potentially useful biomarkers of renal injury. Increases in response to endothelin A antagonism may reflect EDN1 upregulation, which may partly explain fluid retention with these agents.

Clinical trial registration: URL: www.clinicalTrials.gov Unique identifier: NCT00810732.

Keywords: CKD; antagonists; endothelin; fluid retention.

© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1.
Figure 1.
Schematic outline of the amino acid structure of preproET‐1 indicating the peptides generated by post‐translational processing. Positions of ELDP (preproET‐1[93–166]) and CT‐proET‐1 (preproET‐1[169–212]) are shown. ET‐1 is produced from big ET‐1 by endothelin‐converting enzyme. CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide; ET‐1, endothelin 1; preproET‐1, prepro‐endothelin‐1.
Figure 2.
Figure 2.
Plasma ELDP (A) and CT‐proET‐1 (C) by stage of CKD and relationship between plasma ELPD (B) and CT‐proET‐1 (D) and eGFR. *P<0.001, **P<0.0001 compared with non‐CKD control subjects (stage 0). For correlation between plasma ELDP and eGFR, r=0.51, P<0.0001. For correlation between plasma CT‐proET‐1 and eGFR, r=0.54, P<0.0001. CKD indicates chronic kidney disease; CT‐proET‐1, C‐terminal pro‐endothelin‐1; eGFR, estimated glomerular filtration rate; ELDP, endothelin‐like domain peptide.
Figure 3.
Figure 3.
Urine ELDP by stage of CKD (A) and relationship between urine ELPD and eGFR (B). CKD indicates chronic kidney disease; eGFR, estimated glomerular filtration rate; ELDP, endothelin‐like domain peptide.
Figure 4.
Figure 4.
Correlation of plasma ELDP with CT‐proET‐1 (r=0.63, P<0.0001). CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide.
Figure 5.
Figure 5.
Percentage change from baseline in plasma ELDP (A) and plasma CT‐proET‐1 (B) following 3 and 6 weeks of treatment with placebo (open bar), sitaxentan (dark grey bar), and nifedipine (light grey bar) (mean±SEM, *P<0.0001 for sitaxentan at 3 or 6 weeks vs baseline). CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide.
Figure 6.
Figure 6.
Relationships between plasma ELDP (A) and plasma CT‐proET‐1 (B) and urine sodium excretion following 6 weeks of treatment with sitaxentan. CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide.
Figure 7.
Figure 7.
Relationships between plasma ELDP and plasma CT‐proET‐1 and urine sodium excretion following 6 weeks treatment with placebo (A and B) and nifedipine (C and D). CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide.

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Source: PubMed

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