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Peer-reviewedCC BY 4.0Cells

Hyperglycemia-Induced Loss of Astrocytic Kir4.1 Is Associated with Increased DNMT1 Activity and Altered AMPK/SIRT1 Signaling

  • Jadier Colón-Vázquez1
  • Yanitza Hernández-Santiago1
  • Christian J. Malpica-Nieves2,3
  • Nathaly M. Rosado-Rivera4
  • Joshua J. Navedo-Jackson1
  • Arelys A. Angueira-Laureano5
  • Miguel P. Méndez-González1,6,7
  • Yuriy Kucheryavykh1
  • Misty J. Eaton1
  • Serguei N. Skatchkov1,3
  • David E. Rivera-Aponte8
8 affiliations
  1. 1Department of Biochemistry, Universidad Central del Caribe, Bayamon, PR 00956, USA
  2. 2School of Chiropractic, Universidad Central del Caribe, Bayamon, PR 00956, USA
  3. 3Department of Physiology, Universidad Central del Caribe, Bayamon, PR 00956, USA
  4. 4Department of Biochemistry, University of Puerto Rico Medical Science, San Juan, PR 00921, USA
  5. 5School of Medicine, University of Puerto Rico Medical Science, San Juan, PR 00921, USA
  6. 6Department of Natural Sciences, University of Puerto Rico, Aguadilla, PR 00603, USA
  7. 7Department of Sciences and Technology, Antillean Adventist University, Mayagüez, PR 00680, USA
  8. 8Department of Biology, University of Puerto Rico, Bayamon, PR 00959, USA
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Abstract

The effects of chronic hyperglycemia on CNS, glial homeostasis and Kir4.1 regulation is poorly understood. Elevated blood glucose levels affect polyamine-sensitive inwardly rectifying potassium channels, Kir4.1, in astrocytes and retinal Müller glial cells. These cells regulate extracellular potassium and clear glutamate, processes supported by Kir4.1. Dysregulation of Kir4.1 channels has been implicated in glutamate toxicity, epilepsy, ataxia, and diabetes-induced neurodegeneration. In this study, we used Tandem Mass Tag Proteomic analysis, Pyrosequencing, SDS-PAGE and Western blot analysis, in whole brain and astrocytic primary cultures in hyperglycemic conditions testing DNMT1 and AMPK activities with RG-108, compound C, and AICAR treatments to investigate how hyperglycemia alters Kir4.1 expression in astrocytes and explored two regulatory mechanisms: (i) DNA methylation mediated by DNA methyltransferase 1 (DNMT-1), which uses S-adenosylmethionine (SAM) as a methyl donor, and (ii) metabolic signaling via the AMPK/SIRT-1 cascade. We found that hyperglycemia (25 mM glucose) (i) increased DNMT-1 protein levels in astrocytes by 1.5–2-fold and (ii) decreased AMPK and (iii) SIRT-1 levels, accompanied by a reduction in Kir4.1 protein expression. Pharmacological inhibition of DNMT-1 with RG-108 decreased DNMT-1 levels and restored Kir4.1. Treatment with AICAR, a selective AMPK activator, rescued SIRT-1 and Kir4.1 expression. In summary, hyperglycemia engages dual regulatory pathways: (i) epigenetic via DNMT-1 and (ii) metabolic via AMPK/SIRT-1, which converge on Kir4.1 downregulation in astrocytes. Therefore, both DNMT-1 inhibition and AMPK activation rescued Kir4.1 expression, suggesting functional support for potassium and glutamate homeostasis and membrane potential stability in glia.

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Cite

BibTeXRIS
BibTeX
@article{colonvazquez2026hyperglycemiainduced,
  title = {{Hyperglycemia-Induced Loss of Astrocytic Kir4.1 Is Associated with Increased DNMT1 Activity and Altered AMPK/SIRT1 Signaling}},
  author = {Jadier Colón-Vázquez and Yanitza Hernández-Santiago and Christian J. Malpica-Nieves and Nathaly M. Rosado-Rivera and Joshua J. Navedo-Jackson and Arelys A. Angueira-Laureano and Miguel P. Méndez-González and Yuriy Kucheryavykh and Misty J. Eaton and Serguei N. Skatchkov and David E. Rivera-Aponte},
  journal = {Cells},
  year = {2026},
  month = oct,
  doi = {10.3390/cells15201906},
  url = {https://www.mdpi.com/2073-4409/15/20/1906},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Hyperglycemia-Induced Loss of Astrocytic Kir4.1 Is Associated with Increased DNMT1 Activity and Altered AMPK/SIRT1 Signaling
AU  - Jadier Colón-Vázquez
AU  - Yanitza Hernández-Santiago
AU  - Christian J. Malpica-Nieves
AU  - Nathaly M. Rosado-Rivera
AU  - Joshua J. Navedo-Jackson
AU  - Arelys A. Angueira-Laureano
AU  - Miguel P. Méndez-González
AU  - Yuriy Kucheryavykh
AU  - Misty J. Eaton
AU  - Serguei N. Skatchkov
AU  - David E. Rivera-Aponte
PY  - 2026
DA  - 2026/10/20
JO  - Cells
DO  - 10.3390/cells15201906
UR  - https://www.mdpi.com/2073-4409/15/20/1906
AB  - The effects of chronic hyperglycemia on CNS, glial homeostasis and Kir4.1 regulation is poorly understood. Elevated blood glucose levels affect polyamine-sensitive inwardly rectifying potassium channels, Kir4.1, in astrocytes and retinal Müller glial cells. These cells regulate extracellular potassium and clear glutamate, processes supported by Kir4.1. Dysregulation of Kir4.1 channels has been implicated in glutamate toxicity, epilepsy, ataxia, and diabetes-induced neurodegeneration. In this study, we used Tandem Mass Tag Proteomic analysis, Pyrosequencing, SDS-PAGE and Western blot analysis, in whole brain and astrocytic primary cultures in hyperglycemic conditions testing DNMT1 and AMPK activities with RG-108, compound C, and AICAR treatments to investigate how hyperglycemia alters Kir4.1 expression in astrocytes and explored two regulatory mechanisms: (i) DNA methylation mediated by DNA methyltransferase 1 (DNMT-1), which uses S-adenosylmethionine (SAM) as a methyl donor, and (ii) metabolic signaling via the AMPK/SIRT-1 cascade. We found that hyperglycemia (25 mM glucose) (i) increased DNMT-1 protein levels in astrocytes by 1.5–2-fold and (ii) decreased AMPK and (iii) SIRT-1 levels, accompanied by a reduction in Kir4.1 protein expression. Pharmacological inhibition of DNMT-1 with RG-108 decreased DNMT-1 levels and restored Kir4.1. Treatment with AICAR, a selective AMPK activator, rescued SIRT-1 and Kir4.1 expression. In summary, hyperglycemia engages dual regulatory pathways: (i) epigenetic via DNMT-1 and (ii) metabolic via AMPK/SIRT-1, which converge on Kir4.1 downregulation in astrocytes. Therefore, both DNMT-1 inhibition and AMPK activation rescued Kir4.1 expression, suggesting functional support for potassium and glutamate homeostasis and membrane potential stability in glia.
SN  - 2073-4409
ER  -