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Author Notes:

Gerardo Gamba, Molecular Physiology Unit, Vasco de Quiroga No. 15, Tlalpan 14000, Mexico City, Mexico. Phone: 5255-5513-3868, gamba@biomedicas.unam.mx.

We thank Dr. Dario Alessi from the MRC phosphorylation unit, Dundee University for providing us with the phosphor-T58-NCC antibody.

Authors reported no disclosures.

Subjects:

Research Funding:

M.C-C was supported by a scholarship from CONACYT-Mexico; and is a graduate student in the Biomedical Science Ph.D. programs of the Universidad Nacional Autónoma de México.

Supported in part by the Leducq Foundation Transatlantic Network on Hypertension and CONACYT Grant 165815 (to G.G.); the NIH K08 DK081728 (to B.K.) and R01 DK-085097 (to R.S.H.); and the Research Service, Atlanta VA Medical Center (R.S.H.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Peripheral Vascular Disease
  • Cardiovascular System & Cardiology
  • distal convoluted tubule
  • hypertension
  • obesity
  • salt transport
  • thiazide
  • with no lysine kinase 3
  • NA+-CL-COTRANSPORTER
  • BLOOD-PRESSURE
  • ANGIOTENSIN-II
  • NEW-MODEL
  • IN-VIVO
  • SODIUM
  • PHOSPHORYLATION
  • EXPRESSION
  • ENAC
  • NCC

Insulin increases the functional activity of the renal NaCl cotransporter

Tools:

Journal Title:

Journal of Hypertension

Volume:

Volume 31, Number 2

Publisher:

, Pages 303-311

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Objectives: Insulin is recognized to increase renal salt reabsorption in the distal nephron and hyperinsulinemic states have been shown to be associated with increased expression of the renal NaCl cotransporter (NCC). However, the effect of insulin on NCC functional activity has not been reported. Methods: Using a heterologous expression system of Xenopus laevis oocytes, a mouse distal convoluted cell line, mDCT15 cells, endogenously expressing NCC, and an ex-vivo kidney perfusion technique, we assessed the effect of insulin on the activity and phosphorylation of NCC. The signaling pathway involved was analyzed. Results: In Xenopus oocytes insulin increases the activity of NCC together with its phosphorylation at threonine residue 58. Activation of NCC by insulin was also observed in mDCT15 cells. Additionally, insulin increased the NCC phosphorylation in kidney under the ex-vivo perfusion technique. In oocytes and mDCT15 cells, insulin effect on NCC was prevented with inhibitors of phosphatidylinositol 3-kinase (PI3K), mTORC2, and AKT1 kinases, but not by inhibitors of MAP or mTORC1 kinases, suggesting that PI3K-mTORC2-AKT1 is the intracellular pathway required. Additionally, activation of NCC by insulin was not affected by wild-type or mutant versions of with no lysine kinase 1, with no lysine kinase 4, or serum glucocorticoid kinase 1, but it was no longer observed in the presence of wild-type or the dominant negative, catalytically inactive with no lysine kinase 3, implicating this kinase in the process. Conclusion: Insulin induces activation and phosphorylation of NCC. This effect could play an important role in arterial hypertension associated with hyperinsulinemic states, such as obesity, metabolic syndrome, or type 2 diabetes mellitus.

Copyright information:

© 2013 Wolters Kluwer Health | Lippincott Williams Wilkins.

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