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The Cl−/HCO3− exchanger pendrin is downregulated during oral co-administration of exogenous mineralocorticoid and KCl in patients with primary aldosteronism

Journal of Human Hypertension volume 35, pages 837–848 (2021)Cite this article

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Abstract

In primary aldosteronism (PA), the occurrence of K+ loss and hypertension suggest alterations in renal tubular transport, but the molecular basis of these alterations in humans is unclear. In this study, urinary extracellular vesicles (uEVs) isolated from patients undergoing fludrocortisone suppression testing (FST, as a means of confirming or excluding PA) were analyzed using mass spectrometry-based proteomics to determine the combined effects of an aldosterone analogue, NaCl and KCl supplementation on renal tubular protein abundance. Of quantified proteins, the Cl−/HCO3− exchanger pendrin decreased by a median 37% [−15, 57] (P < 0.01) and the potassium channel ROMK increased by a median 31% [−10, 85] (P < 0.01) during FST among 10 PA subjects. The trends remained, but to a lesser degree, in two subjects cured of PA by unilateral adrenalectomy. In PA subjects, plasma K+ increased from median 3.6 to 4.2 mM (P < 0.01) and 24 h urine K+ from 101 to 202 mmol (P < 0.01), while 24 h urine Na+/K+ decreased from 2.3 to 0.8 (P < 0.01). At baseline, pendrin negatively correlated with plasma K+ (P < 0.05) and positively correlated with plasma aldosterone (P < 0.01). There were no clear correlations between Δ pendrin (Δ = D4–D0) and changes in blood or urine variables, and no correlations between ROMK in any of the blood or urine variables either at baseline or during FST. We conclude that oral co-administration of mineralocorticoid and KCl in PA patients is associated with reduced pendrin and enhanced ROMK in uEVs. Pendrin reduction during FST suggests that the suppressive effects of oral KCl may outweigh pendrin upregulation by mineralocorticoids.

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Fig. 1: Venn diagram summarizing quantified proteins and their overlap with Vesiclepedia, Exocarta and a renal transport protein database.
Fig. 2: Volcano plot depicting differentially abundant proteins affected by FST in 10 non-operated PA subjects.
Fig. 3: Changes in Pendrin, ROMK and EV markers (TSG101 and CD9) in non-operated and operated subjects who underwent FST.
Fig. 4: Baseline correlations and differences.

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Data availability

The MS data have been deposited to the ProteomeXchange Consortium via the PRIDE (add reference: https://www.nature.com/articles/nbt.2839) partner repository with the dataset identifier PXD017083 (Reviewer account details: username: reviewer92263@ebi.ac.uk, password: 4PUMbpN2).

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Acknowledgements

AW is supported by a scholarship from the Commonwealth Government of Australia. This work is supported by a grant from the Leducq Foundation (Potassium in Hypertension Network). Further funding to RAF is provided by the Novo Nordisk Foundation and the Danish Independent Research Fund: Medical Sciences.

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Authors and Affiliations

  1. Endocrine Hypertension Research Centre, The University of Queensland Faculty of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, QLD, Australia

    Aihua Wu, Martin J. Wolley, Richard D. Gordon & Michael Stowasser

  2. Department of Nephrology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Martin J. Wolley

  3. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Qi Wu & Robert A. Fenton

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Wu, A., Wolley, M.J., Wu, Q. et al. The Cl−/HCO3− exchanger pendrin is downregulated during oral co-administration of exogenous mineralocorticoid and KCl in patients with primary aldosteronism. J Hum Hypertens 35, 837–848 (2021). https://doi.org/10.1038/s41371-020-00439-7

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