Excitatory GABAergic action and increased vasopressin synthesis in hypothalamic magnocellular neurosecretory cells underlie the high plasma level of vasopressin in diabetic rats

Young Beom Kim, Woong Bin Kim, Won Woo Jung, Xiangyan Jin, Yoon Sik Kim, Byoungjae Kim, Hee Chul Han, Gene D. Block, Christopher S. Colwell, Yang In Kim

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Diabetes mellitus (DM) is associated with increased plasma levels of arginine-vasopressin (AVP), which may aggravate hyperglycemia and nephropathy. However, themechanisms by which DM may cause the increased AVP levels are not known. Electrophysiological recordings in supraoptic nucleus (SON) slices from streptozotocin (STZ)-induced DM rats and vehicle-treated control rats revealed that γ-aminobutyric acid (GABA) functions generally as an excitatory neurotransmitter in the AVP neurons of STZ rats, whereas it usually evokes inhibitory responses in the cells of control animals. Furthermore,Western blotting analyses of Cl- transporters in the SON tissues indicated that Na+-K+-2CΓ- cotransporter isotype 1 (a Cl- importer) was upregulated and K+-Cl- cotransporter isotype 2 (KCC2; a Cl- extruder) was downregulated in STZ rats. Treatment with CLP290 (a KCC2 activator) significantly lowered blood AVP and glucose levels in STZ rats. Last, investigation that used rats expressing an AVP-enhanced green fluorescent protein fusion gene showed that AVP synthesis in AVP neurons was much more intense in STZ rats than in control rats. We conclude that altered Cl- homeostasis that makes GABA excitatory and enhanced AVP synthesis are important changes in AVP neurons thatwould increase AVP secretion in DM. Our data suggest that Cl- transporters in AVP neurons are potential targets of antidiabetes treatments.

Original languageEnglish
Pages (from-to)486-495
Number of pages10
JournalDiabetes
Volume67
Issue number3
DOIs
Publication statusPublished - 2018 Mar 1

Bibliographical note

Funding Information:
Acknowledgments. The authors are grateful to Dr. Y. Ueta (University of Occupational and Environmental Health, Kitakyushu, Japan), Dr. Y. De Koninck (Université Laval, Québec, Canada), and Dr. C. Lidsley (Vanderbilt University, Nashville, TN) for providing rats expressing AVP-eGFP and OXT-mRFP1 fusion genes, KCC2 activators (CLP257, CLP290), and the KCC2 inhibitor (VU0463271), respectively. Funding. This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (Ministry of Science, Information and Communications Technology and Future Planning) (2016R1D1A1B03932771 to Y.-B.K. and 2014R1A2A1A11049900 and 2017R1A2B2002277 to Y.I.K.). Y.-B.K., W.B.K., Y.S.K., and Y.I.K. were supported by the Brain Korea 21 Project from 2009 to 2017. Y.S.K. and C.S.C. received support from the O’Keefe Foundation. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. Y.-B.K., W.B.K., H.C.H., G.D.B., C.S.C., and Y.I.K. conceived this project. Y.-B.K., W.B.K., W.W.J., X.J., Y.S.K., and B.K. performed the experiments and analyzed the results. Y.-B.K., W.B.K., C.S.C., and Y.I.K. wrote the manuscript. Y.I.K. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Information:
This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (Ministry of Science, Information and Communications Technology and Future Planning) (2016R1D1A1B03932771 to Y.-B.K. and 2014R1A2A1A11049900 and 2017R1A2B2002277 to Y.I.K.). Y.-B.K., W.B.K., Y.S.K., and Y.I.K. were supported by the Brain Korea 21 Project from 2009 to 2017. Y.S.K. and C.S.C. received support from the O'Keefe Foundation.

Publisher Copyright:
© 2017 by the American Diabetes Association.

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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