title: In Primary Aldosteronism, Mineralocorticoids Influence Exosomal Sodium-Chloride Cotransporter Abundance.
abstract: Distal tubular sodium retention is a potent driver of hypertension, and the thiazide-sensitive sodium-chloride cotransporter (NCC) has a key role in this process. In humans, factors regulating NCC are unclear, but in animal models, aldosterone is a potent regulator, possibly via effects on plasma potassium. We studied the effects of the mineralocorticoid fludrocortisone on the abundance of NCC and its phosphorylated form (pNCC) as well as WNK lysine deficient protein kinase 4 (WNK4) and STE20/SPS1-related, proline alanine-rich kinase (SPAK) in human urinary exosomes. We isolated exosomes from daily urine samples in 25 patients undergoing fludrocortisone suppression testing (100 μg every 6 hours for 4 days) to diagnose or exclude primary aldosteronism. Over the course of the test, NCC levels increased 3.68-fold (P<0.01) and pNCC levels increased 2.73-fold (P<0.01) relative to baseline. The ratio of pNCC/NCC dropped by 48% (P<0.01). The abundance of WNK4 increased 3.23-fold (P<0.01), but SPAK abundance did not change significantly (P=0.14). Plasma potassium concentration strongly and negatively correlated with pNCC, NCC, and WNK4 abundance (P<0.001 for all). This study shows that, in humans, mineralocorticoid administration is associated with a rapid increase in abundance of NCC and pNCC, possibly via the WNK pathway. These effects may be driven by changes in plasma potassium.
authors.affiliation: Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia.|Department of Nephrology, Royal Brisbane and Women's Hospital, Brisbane, Australia; and.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wolley
authors.affiliation: Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia.
authors.forename: Aihua
authors.initials: A
authors.lastname: Wu
authors.affiliation: Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia.
authors.forename: Shengxin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gordon
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenton
authors.affiliation: Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia; m.stowasser@uq.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Stowasser
mesh_terms: D055354:Exosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008901:Mineralocorticoids / Q000378:metabolism*; D049992:Sodium Chloride Symporters / Q000502:physiology*
chemical_list: D008901:Mineralocorticoids; D049992:Sodium Chloride Symporters
keywords: Exosomes; NCC; Na transport; aldosterone