Mechanism of Oxidative DNA Damage in Diabetes

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. Akt and tuberin, 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. RESEARCH DESIGN AND METHODS-Phosphorylation ofRESULTS-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 N-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. Diabetes

Triphlorethol-A Improves the Non-Homologous End Joining and Base-Excision Repair Capacity Impaired by Formaldehyde

“…In a previous study, Kang et al (2009) demonstrated that OGG1 induced this via the activation of the PI3K/Akt pathway. In contrast, Simone et al (2008) found that inhibition of PI3K/Akt reversed the OGG1 expression downregulated by high glucose treatment in the renal cortex of diabetic rats. Therefore, the relationships of DNA-PKcs, Ku heterodimer, and OGG1 to PI3K/Akt need to be elucidated in future.…”

Diabetes and renal tubular cell apoptosis

“…Prolonged exposure (1-13 d) of proximal tubular epithelial cells to hyperglycemic environment has been shown to inhibit cell proliferation and induce growth arrest or cellular MINIREVIEWS apoptosis [8][9][10][11][12] . These cellular effects are caused by the activation of a network of intracellular signaling pathways and include the phosphatidylinostiol 3 kinase (PI3 kinase)/adams kara taylor (AKT) signaling pathway [13] . Activation of PI3 kinase and phosphorylation of serine/threonine kinase AKT/protein kinase B (PKB) by insulin, insulin like growth factors in human embryonic 293 (HEK-293) and HeLa cells lead to inactivation of tuberin by phosphorylating at Ser939, Ser1086/1088 and Thr1422 [14,15] .…”

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

“…Glucose serves as an energy source in virtually all eukaryotic cells. A high concentration of glucose increases the metabolic input into cells and consequently induces oxidative stress via ROS production, thereby inducing DNA, protein, and lipid damage, causing premature senescence (Mortuza, Chen, Feng, Sen, & Chakrabarti, 2013; Simone, Gorin, Velagapudi, Abboud, & Habib, 2008). …”

“…AKT also activates the mechanistic target of rapamycin (mTOR) and induces cellular senescence (Johnson, Rabinovitch, & Kaeberlein, 2013). Furthermore, high glucose levels stimulate protein synthesis and induce ROS production by AKT phosphorylation (Sheu, Ho, Chao, Kuo, & Liu, 2004; Simone et al, 2008). …”