In primary aldosteronism, mineralocorticoids influence exosomal sodium-chloride cotransporter abundance

Wolley, Martin J., Wu, Aihua, Xu, Shengxin, Gordon, Richard D., Fenton, Robert A. and Stowasser, Michael (2017) In primary aldosteronism, mineralocorticoids influence exosomal sodium-chloride cotransporter abundance. Journal of the American Society of Nephrology, 28 1: 56-63. doi:10.1681/ASN.2015111221


Author Wolley, Martin J.
Wu, Aihua
Xu, Shengxin
Gordon, Richard D.
Fenton, Robert A.
Stowasser, Michael
Title In primary aldosteronism, mineralocorticoids influence exosomal sodium-chloride cotransporter abundance
Journal name Journal of the American Society of Nephrology   Check publisher's open access policy
ISSN 1046-6673
1533-3450
Publication date 2017-01-01
Year available 2016
Sub-type Article (original research)
DOI 10.1681/ASN.2015111221
Open Access Status Not yet assessed
Volume 28
Issue 1
Start page 56
End page 63
Total pages 8
Place of publication Washington, DC, United States
Publisher American Society of Nephrology
Language eng
Subject 2727 Nephrology
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 mg 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.
Formatted 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.
Keyword NCC
Aldosterone
Na transport
Exosomes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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