Mechanism of DNA damage in Diabetes

Abstract

Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, AND Geriatric Research, Education and Clinical CTR, South Texas veterans Health System, San Antonio, 78229 TX S complications are the major causes of morbidity and mortality in patients with diabetes. Oxidative stress leads to protein, lipid, and DNA modifi cations that cause cellular dysfunction and contribute to the pathogenesis of macroand microvascular complications of diabetes, including diabetic nephropathy. Mitochondrion and nucleus, two major targets of oxidative stress, contain a variety of DNA repair enzymes to repair oxidant-induced DNA modifi cations. Damage most likely occurs when the endogenous antioxidant network and DNA repair systems are overwhelmed. However, it is essential for the cell to repair DNA damage induced by oxidants. 8-Oxo-7,8-dihydro2’-deoxyguanosine (8-oxodG) is a sensitive marker of reactive oxygen species (ROS)– induced DNA damage. Th ere is an increase in 8-oxodG levels in tissue of diabetic rats and in the urine of patients with type 1 and type 2 diabetes, with the levels being signifi cantly higher in patients with albuminuria or with other diabetic complications. 8-OxodG in DNA is repaired primarily via the DNA base excision repair pathway. Th e DNA repair enzyme that recognizes and excises 8-oxodG is 8-oxoG-DNA glycosylase (OGG1). Defi ciency in DNA repair enzyme OGG1 has important functional consequences, compromising the ability of cells to repair DNA. We have recently shown that OGG1 is regulated by tuberin, the product of the tumor suppressor gene, TSC-2. Tuberin normally exists in an active state physically bound to hamartin, the product of TSC-1 gene, to form a stable complex. Th ese two proteins function within the same pathway(s) regulating cell cycle, cell growth, adhesion, and vesicular traffi cking. Activation of phosphatidylinositol 3-kinase (PI 3-kinase) and phosphorylation of serine/threonine kinase Akt/protein kinase B (PKB) by certain agonists lead to inactivation of tuberin. Th e PI 3-kinase/ Akt pathway is activated in diabetes, and there is evidence that this activation is redox dependent in diff erent cell types, including renal cells. Little is known about DNA repair disturbances potentially contributing to DNA damage in diabetes. In the present study, we determined a potential mechanism by which ROS result in 8-oxodG accumulation and explored the role of tuberin phosphorylation and OGG1 in the kidney cortex of rats with type 1 diabetes. Samy L Habib, J Diabetes Metab, 2:8 doi: http://dx.doi.org/10.4172/2155-6156.S1.12