In the present study, we investigated the activity of the thiazide-sensitive NCC (Na+–Cl− co-transporter) in experimental metabolic syndrome and the role of insulin in NCC activation. Renal responses to the NCC inhibitor HCTZ (hydrochlorothiazide), as a measure of NCC activity in vivo, were studied in 12-week-old ZO (Zucker obese) rats, a model of the metabolic syndrome, and in ZL (Zucker lean) control animals, together with renal NCC expression and molecular markers of NCC activity, such as localization and phosphorylation. Effects of insulin were studied further in mammalian cell lines with inducible and endogenous expression of this molecule. ZO rats displayed marked hyperinsulinaemia, but no differences in plasma aldosterone, compared with ZL rats. In ZO rats, natriuretic and diuretic responses to NCC inhibition with HCTZ were enhanced compared with ZL rats, and were associated with a decrease in BP (blood pressure). ZO rats displayed enhanced Thr53 NCC phosphorylation and predominant membrane localization of both total and phosphorylated NCC, together with a different profile in expression of SPAK (Ste20-related proline/alanine-rich kinase) isoforms, and lower expression of WNK4. In vitro, insulin induced NCC phosphorylation, which was blocked by a PI3K (phosphoinositide 3-kinase) inhibitor. Insulin-induced reduction in WNK4 expression was also observed, but delayed compared with the time course of NCC phosphorylation. In summary, we report increased NCC activity in hyperinsulinaemic rodents in conjunction with the SPAK expression profile consistent with NCC activation and reduced WNK4, as well as an ability of insulin to induce NCC stimulatory phosphorylation in vitro. Together, these findings indicate that hyperinsulinaemia is an important driving force of NCC activity in the metabolic syndrome with possible consequences for BP regulation.
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December 2012
Research Article|
August 01 2012
Enhanced phosphorylation of Na+–Cl− co-transporter in experimental metabolic syndrome: role of insulin
Radko Komers
;
1Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR 97239, U.S.A.
Correspondence: Dr Radko Komers (email komersr@ohsu.edu).
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Shaunessy Rogers
;
Shaunessy Rogers
1Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR 97239, U.S.A.
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Terry T. Oyama
;
Terry T. Oyama
1Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR 97239, U.S.A.
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Bei Xu
;
Bei Xu
1Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR 97239, U.S.A.
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Chao-Ling Yang
;
Chao-Ling Yang
1Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR 97239, U.S.A.
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James McCormick
;
James McCormick
1Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR 97239, U.S.A.
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David H. Ellison
David H. Ellison
1Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR 97239, U.S.A.
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Clin Sci (Lond) (2012) 123 (11): 635–647.
Article history
Received:
January 12 2012
Revision Received:
May 07 2012
Accepted:
May 31 2012
Accepted Manuscript online:
May 31 2012
Citation
Radko Komers, Shaunessy Rogers, Terry T. Oyama, Bei Xu, Chao-Ling Yang, James McCormick, David H. Ellison; Enhanced phosphorylation of Na+–Cl− co-transporter in experimental metabolic syndrome: role of insulin. Clin Sci (Lond) 1 December 2012; 123 (11): 635–647. doi: https://doi.org/10.1042/CS20120003
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