RGD Reference Report - Mechanism of oxidative DNA damage in diabetes: tuberin inactivation and downregulation of DNA repair enzyme 8-oxo-7,8-dihydro-2'-deoxyguanosine-DNA glycosylase. - Rat Genome Database

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

Authors: Simone, S  Gorin, Y  Velagapudi, C  Abboud, HE  Habib, SL 
Citation: Simone S, etal., Diabetes. 2008 Oct;57(10):2626-36. doi: 10.2337/db07-1579. Epub 2008 Jul 3.
RGD ID: 8657153
Pubmed: PMID:18599524   (View Abstract at PubMed)
PMCID: PMC2551671   (View Article at PubMed Central)
DOI: DOI:10.2337/db07-1579   (Journal Full-text)

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 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AKT1HumanExperimental Diabetes Mellitus  ISOAkt1 (Rattus norvegicus)protein:increased serine phosphorylation:cortex of kidney RGD 
Akt1RatExperimental Diabetes Mellitus  IEP protein:increased serine phosphorylation:cortex of kidney RGD 
Akt1MouseExperimental Diabetes Mellitus  ISOAkt1 (Rattus norvegicus)protein:increased serine phosphorylation:cortex of kidney RGD 
OGG1HumanExperimental Diabetes Mellitus  ISOOgg1 (Rattus norvegicus) RGD 
Ogg1RatExperimental Diabetes Mellitus  IEP  RGD 
Ogg1MouseExperimental Diabetes Mellitus  ISOOgg1 (Rattus norvegicus) RGD 
TSC2HumanExperimental Diabetes Mellitus  ISOTsc2 (Rattus norvegicus)protein:increased threonine phosphorylation:cortex of kidney RGD 
Tsc2RatExperimental Diabetes Mellitus  IEP protein:increased threonine phosphorylation:cortex of kidney RGD 
Tsc2MouseExperimental Diabetes Mellitus  ISOTsc2 (Rattus norvegicus)protein:increased threonine phosphorylation:cortex of kidney RGD 

Objects Annotated

Genes (Rattus norvegicus)
Akt1  (AKT serine/threonine kinase 1)
Ogg1  (8-oxoguanine DNA glycosylase)
Tsc2  (TSC complex subunit 2)

Genes (Mus musculus)
Akt1  (thymoma viral proto-oncogene 1)
Ogg1  (8-oxoguanine DNA-glycosylase 1)
Tsc2  (TSC complex subunit 2)

Genes (Homo sapiens)
AKT1  (AKT serine/threonine kinase 1)
OGG1  (8-oxoguanine DNA glycosylase)
TSC2  (TSC complex subunit 2)


Additional Information