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Novel protective mechanism of reducing renal cell damage in diabetes: Activation AMPK by AICAR increased NRF2/OGG1 proteins and reduced oxidative DNA damage
- Source :
- Cell cycle (Georgetown, Tex.), vol 15, iss 22
- Publication Year :
- 2016
- Publisher :
- Taylor & Francis, 2016.
-
Abstract
- Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression. In addition, activation of AMPK by AICAR resulted in an increase raptor phosphorylation at Ser792 and leads to increase the promoter activity of OGG1 through upregulation of Nrf2. Downregulation of AMPK by DN-AMPK and raptor and Nrf2 by siRNA resulted in significant decease in promoter activity and protein expression of OGG1. On the other hand, downregulation of Akt by DN-Akt and rictor by siRNA resulted in significant increase in promoter activity and protein expression of Nrf2 and OGG1. Moreover, gel shift analysis shows reduction of Nrf2 binding to OGG1 promoter in cells treated with HG while cells treated with AICAR reversed the effect of HG. Furthermore, db/db mice treated with AICAR show significant increased in AMPK and raptor phosphroylation as well as OGG1 and Nrf2 protein expression that associated with significant decrease in oxidative DNA damage (8-oxodG) compared to non-treated mice. In summary, our data provide a novel protective mechanism by which AICAR prevents renal cell damage in diabetes and the consequence complications of hyperglycemia with a specific focus on nephropathy.
- Subjects :
- AMPK
0301 basic medicine
Kidney Disease
Messenger
AMP-Activated Protein Kinases
Kidney
DNA Glycosylases
Kidney Tubules, Proximal
Mice
0302 clinical medicine
Models
Promoter Regions, Genetic
OGG1
diabetes
TOR Serine-Threonine Kinases
Proximal
Adaptor Proteins
Up-Regulation
Cell biology
Kidney Tubules
medicine.anatomical_structure
030220 oncology & carcinogenesis
mTOR
Phosphorylation
Protein Binding
medicine.medical_specialty
NF-E2-Related Factor 2
DNA repair
1.1 Normal biological development and functioning
AICAR
Renal and urogenital
Down-Regulation
Mechanistic Target of Rapamycin Complex 1
Biology
Models, Biological
Nrf2
Promoter Regions
03 medical and health sciences
Genetic
Downregulation and upregulation
Underpinning research
Report
Internal medicine
Genetics
Diabetes Mellitus
medicine
Animals
Humans
RNA, Messenger
Molecular Biology
Protein kinase B
Cell damage
Metabolic and endocrine
PI3K/AKT/mTOR pathway
Adaptor Proteins, Signal Transducing
Base Sequence
Prevention
Signal Transducing
Regulatory-Associated Protein of mTOR
Cell Biology
Ribonucleotides
Biological
Aminoimidazole Carboxamide
medicine.disease
Enzyme Activation
Oxidative Stress
Glucose
HEK293 Cells
Rapamycin-Insensitive Companion of mTOR Protein
030104 developmental biology
Endocrinology
Multiprotein Complexes
RNA
Biochemistry and Cell Biology
Carrier Proteins
Proto-Oncogene Proteins c-akt
DNA Damage
Developmental Biology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Cell cycle (Georgetown, Tex.), vol 15, iss 22
- Accession number :
- edsair.doi.dedup.....bc82f932fd034ec860fd897fa2f9984e
- Full Text :
- https://doi.org/10.6084/m9.figshare.4046598