Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients

Ganesh Pathare; Omar A. Z. Tutakhel; Mark C. van der Wel; Luke M. Shelton; Jaap Deinum; Jacques W. M. Lenders; Joost G. J. Hoenderop; René J. M. Bindels

doi:10.1152/ajprenal.00644.2016

Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients

Ganesh Pathare
, Omar A. Z. Tutakhel
, Mark C. van der Wel
, Luke M. Shelton
, Jaap Deinum
, Jacques W. M. Lenders
, Joost G. J. Hoenderop
, René J. M. Bindels^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

21 Citations (Scopus)

Abstract

The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC_1/2), total NCC (NCC_1-3), and the phosphorylated form of total NCC (pNCC_1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC_1/2, NCC_1-3, and pNCC_1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide. © 2017 the American Physiological Society.

Original language	English
Pages (from-to)	F1063-F1072
Journal	American Journal of Physiology-Renal Physiology
Volume	312
Issue number	6
DOIs	https://doi.org/10.1152/ajprenal.00644.2016
Publication status	Published - 2017
Externally published	Yes

Bibliographical note

Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

Funding

This study was supported by the European Society of Hypertension (2011–2013 Fellowship), the EURenOmics project from the European Union seventh Framework Programme (FP7/2007–2013, agreement no. 305608), the Netherlands Organization for Scientific Research (VENI ZonMw 916.12.046), and the Dutch Kidney Foundation (PHD12.14 and 16OI04).

Research Keywords

Hypertension
Kidney
NaCl cotransporter
Thiazide diuretics
Urinary extracellular vesicles

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10.1152/ajprenal.00644.2016

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Pathare, G., Tutakhel, O. A. Z., van der Wel, M. C., Shelton, L. M., Deinum, J., Lenders, J. W. M., Hoenderop, J. G. J., & Bindels, R. J. M. (2017). Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients. American Journal of Physiology-Renal Physiology, 312(6), F1063-F1072. https://doi.org/10.1152/ajprenal.00644.2016

@article{83663dd771a14fee9a0c97f5c53d43a2,

title = "Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients",

abstract = "The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC1/2), total NCC (NCC1-3), and the phosphorylated form of total NCC (pNCC1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC1/2, NCC1-3, and pNCC1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide. {\textcopyright} 2017 the American Physiological Society.",

keywords = "Hypertension, Kidney, NaCl cotransporter, Thiazide diuretics, Urinary extracellular vesicles",

author = "Ganesh Pathare and Tutakhel, \{Omar A. Z.\} and \{van der Wel\}, \{Mark C.\} and Shelton, \{Luke M.\} and Jaap Deinum and Lenders, \{Jacques W. M.\} and Hoenderop, \{Joost G. J.\} and Bindels, \{Ren{\'e} J. M.\}",

note = "Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].",

year = "2017",

doi = "10.1152/ajprenal.00644.2016",

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Pathare, G, Tutakhel, OAZ, van der Wel, MC, Shelton, LM, Deinum, J, Lenders, JWM, Hoenderop, JGJ & Bindels, RJM 2017, 'Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients', American Journal of Physiology-Renal Physiology, vol. 312, no. 6, pp. F1063-F1072. https://doi.org/10.1152/ajprenal.00644.2016

Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients. / Pathare, Ganesh; Tutakhel, Omar A. Z.; van der Wel, Mark C. et al.
In: American Journal of Physiology-Renal Physiology, Vol. 312, No. 6, 2017, p. F1063-F1072.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients

AU - Pathare, Ganesh

AU - Tutakhel, Omar A. Z.

AU - van der Wel, Mark C.

AU - Shelton, Luke M.

AU - Deinum, Jaap

AU - Lenders, Jacques W. M.

AU - Hoenderop, Joost G. J.

AU - Bindels, René J. M.

N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

PY - 2017

Y1 - 2017

N2 - The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC1/2), total NCC (NCC1-3), and the phosphorylated form of total NCC (pNCC1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC1/2, NCC1-3, and pNCC1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide. © 2017 the American Physiological Society.

AB - The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC1/2), total NCC (NCC1-3), and the phosphorylated form of total NCC (pNCC1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC1/2, NCC1-3, and pNCC1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide. © 2017 the American Physiological Society.

KW - Hypertension

KW - Kidney

KW - NaCl cotransporter

KW - Thiazide diuretics

KW - Urinary extracellular vesicles

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U2 - 10.1152/ajprenal.00644.2016

DO - 10.1152/ajprenal.00644.2016

M3 - RGC 21 - Publication in refereed journal

C2 - 28274929

SN - 1931-857X

VL - 312

SP - F1063-F1072

JO - American Journal of Physiology-Renal Physiology

JF - American Journal of Physiology-Renal Physiology

IS - 6

ER -

Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients

Abstract

Bibliographical note

Funding

Research Keywords

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