Mechanism of oxidative DNA damage in diabetes tuberin inactivation and downregulation of DNA repair enzyme 8-oxo-7,8-dihydro-2′-deoxyguanosine- DNA glycosylase

Simona Simone, Yves Gorin, Chakradhar Velagapudi, Hanna E. Abboud, Samy L Habib

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

OBJECTIVE-To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells. RESEARCH DESIGN AND METHODS-Phosphorylation of Akt and tuberin, 8-oxo-7,8-dihydro-2′- deoxyguanosine (8-oxodG) levels, and 8-oxoG-DNA glycosylase (OGG1) expression were measured in kidney cortical tissue of control and type 1 diabetic animals and in proximal tubular cells incubated with normal or high glucose. RESULTS-In the renal cortex of diabetic rats, the increase in Akt phosphorylation is associated with enhanced phosphorylation of tuberin, decreased OGG1 protein expression, and 8-oxodG accumulation. Exposure of proximal tubular epithelial cells to high glucose causes a rapid increase in reactive oxygen species (ROS) generation that correlates with the increase in Akt and tuberin phosphorylation. High glucose also resulted in downregulation of OGG1 protein expression, paralleling its effect on Akt and tuberin. Inhibition of phosphatidylinositol 3-kinase/ Akt significantly reduced high glucose-induced tuberin phosphorylation and restored OGG1 expression. Hydrogen peroxide stimulates Akt and tuberin phosphorylation and decreases OGG1 protein expression. The antioxidant A-acetylcysteine significantly inhibited ROS generation, Akt/protein kinase B, and tuberin phosphorylation and resulted in deceased 8-oxodG accumulation and upregulation of OGG1 protein expression. CONCLUSIONS-Hyperglycemia in type 1 diabetes and treatment of proximal tubular epithelial cells with high glucose leads to phosphorylation/inactivation of tuberin and downregulation of OGG1 via a redox-dependent activation of Akt in renal tubular epithelial cells. This signaling cascade provides a mechanism of oxidative stress-mediated DNA damage in diabetes.

Original languageEnglish (US)
Pages (from-to)2626-2636
Number of pages11
JournalDiabetes
Volume57
Issue number10
DOIs
StatePublished - Oct 2008
Externally publishedYes

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DNA Glycosylases
DNA Repair Enzymes
DNA Damage
Down-Regulation
Phosphorylation
Epithelial Cells
Glucose
Type 1 Diabetes Mellitus
Kidney
Reactive Oxygen Species
Proteins
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
tuberous sclerosis complex 2 protein
8-oxo-7-hydrodeoxyguanosine
Acetylcysteine
Hyperglycemia
Hydrogen Peroxide
Oxidation-Reduction
Oxidative Stress

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Mechanism of oxidative DNA damage in diabetes tuberin inactivation and downregulation of DNA repair enzyme 8-oxo-7,8-dihydro-2′-deoxyguanosine- DNA glycosylase. / Simone, Simona; Gorin, Yves; Velagapudi, Chakradhar; Abboud, Hanna E.; Habib, Samy L.

In: Diabetes, Vol. 57, No. 10, 10.2008, p. 2626-2636.

Research output: Contribution to journalArticle

Simone, Simona ; Gorin, Yves ; Velagapudi, Chakradhar ; Abboud, Hanna E. ; Habib, Samy L. / Mechanism of oxidative DNA damage in diabetes tuberin inactivation and downregulation of DNA repair enzyme 8-oxo-7,8-dihydro-2′-deoxyguanosine- DNA glycosylase. In: Diabetes. 2008 ; Vol. 57, No. 10. pp. 2626-2636.
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abstract = "OBJECTIVE-To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells. RESEARCH DESIGN AND METHODS-Phosphorylation of Akt and tuberin, 8-oxo-7,8-dihydro-2′- deoxyguanosine (8-oxodG) levels, and 8-oxoG-DNA glycosylase (OGG1) expression were measured in kidney cortical tissue of control and type 1 diabetic animals and in proximal tubular cells incubated with normal or high glucose. RESULTS-In the renal cortex of diabetic rats, the increase in Akt phosphorylation is associated with enhanced phosphorylation of tuberin, decreased OGG1 protein expression, and 8-oxodG accumulation. Exposure of proximal tubular epithelial cells to high glucose causes a rapid increase in reactive oxygen species (ROS) generation that correlates with the increase in Akt and tuberin phosphorylation. High glucose also resulted in downregulation of OGG1 protein expression, paralleling its effect on Akt and tuberin. Inhibition of phosphatidylinositol 3-kinase/ Akt significantly reduced high glucose-induced tuberin phosphorylation and restored OGG1 expression. Hydrogen peroxide stimulates Akt and tuberin phosphorylation and decreases OGG1 protein expression. The antioxidant A-acetylcysteine significantly inhibited ROS generation, Akt/protein kinase B, and tuberin phosphorylation and resulted in deceased 8-oxodG accumulation and upregulation of OGG1 protein expression. CONCLUSIONS-Hyperglycemia in type 1 diabetes and treatment of proximal tubular epithelial cells with high glucose leads to phosphorylation/inactivation of tuberin and downregulation of OGG1 via a redox-dependent activation of Akt in renal tubular epithelial cells. This signaling cascade provides a mechanism of oxidative stress-mediated DNA damage in diabetes.",
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T1 - Mechanism of oxidative DNA damage in diabetes tuberin inactivation and downregulation of DNA repair enzyme 8-oxo-7,8-dihydro-2′-deoxyguanosine- DNA glycosylase

AU - Simone, Simona

AU - Gorin, Yves

AU - Velagapudi, Chakradhar

AU - Abboud, Hanna E.

AU - Habib, Samy L

PY - 2008/10

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N2 - OBJECTIVE-To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells. RESEARCH DESIGN AND METHODS-Phosphorylation of Akt and tuberin, 8-oxo-7,8-dihydro-2′- deoxyguanosine (8-oxodG) levels, and 8-oxoG-DNA glycosylase (OGG1) expression were measured in kidney cortical tissue of control and type 1 diabetic animals and in proximal tubular cells incubated with normal or high glucose. RESULTS-In the renal cortex of diabetic rats, the increase in Akt phosphorylation is associated with enhanced phosphorylation of tuberin, decreased OGG1 protein expression, and 8-oxodG accumulation. Exposure of proximal tubular epithelial cells to high glucose causes a rapid increase in reactive oxygen species (ROS) generation that correlates with the increase in Akt and tuberin phosphorylation. High glucose also resulted in downregulation of OGG1 protein expression, paralleling its effect on Akt and tuberin. Inhibition of phosphatidylinositol 3-kinase/ Akt significantly reduced high glucose-induced tuberin phosphorylation and restored OGG1 expression. Hydrogen peroxide stimulates Akt and tuberin phosphorylation and decreases OGG1 protein expression. The antioxidant A-acetylcysteine significantly inhibited ROS generation, Akt/protein kinase B, and tuberin phosphorylation and resulted in deceased 8-oxodG accumulation and upregulation of OGG1 protein expression. CONCLUSIONS-Hyperglycemia in type 1 diabetes and treatment of proximal tubular epithelial cells with high glucose leads to phosphorylation/inactivation of tuberin and downregulation of OGG1 via a redox-dependent activation of Akt in renal tubular epithelial cells. This signaling cascade provides a mechanism of oxidative stress-mediated DNA damage in diabetes.

AB - OBJECTIVE-To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells. RESEARCH DESIGN AND METHODS-Phosphorylation of Akt and tuberin, 8-oxo-7,8-dihydro-2′- deoxyguanosine (8-oxodG) levels, and 8-oxoG-DNA glycosylase (OGG1) expression were measured in kidney cortical tissue of control and type 1 diabetic animals and in proximal tubular cells incubated with normal or high glucose. RESULTS-In the renal cortex of diabetic rats, the increase in Akt phosphorylation is associated with enhanced phosphorylation of tuberin, decreased OGG1 protein expression, and 8-oxodG accumulation. Exposure of proximal tubular epithelial cells to high glucose causes a rapid increase in reactive oxygen species (ROS) generation that correlates with the increase in Akt and tuberin phosphorylation. High glucose also resulted in downregulation of OGG1 protein expression, paralleling its effect on Akt and tuberin. Inhibition of phosphatidylinositol 3-kinase/ Akt significantly reduced high glucose-induced tuberin phosphorylation and restored OGG1 expression. Hydrogen peroxide stimulates Akt and tuberin phosphorylation and decreases OGG1 protein expression. The antioxidant A-acetylcysteine significantly inhibited ROS generation, Akt/protein kinase B, and tuberin phosphorylation and resulted in deceased 8-oxodG accumulation and upregulation of OGG1 protein expression. CONCLUSIONS-Hyperglycemia in type 1 diabetes and treatment of proximal tubular epithelial cells with high glucose leads to phosphorylation/inactivation of tuberin and downregulation of OGG1 via a redox-dependent activation of Akt in renal tubular epithelial cells. This signaling cascade provides a mechanism of oxidative stress-mediated DNA damage in diabetes.

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