Novel protective mechanism of reducing renal cell damage in diabetes: Activation AMPK by AICAR increased NRF2/OGG1 proteins and reduced oxidative DNA damage.
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 Ser792and 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.
a Department of Cellular and Structural Biology , University of Texas Health Science Center , San Antonio , TX , USA.|b Geriatric Research, Education and Clinical Department , South Texas Veterans Health Care System , San Antonio , TX , USA.
Samy L
SL
Habib
a Department of Cellular and Structural Biology , University of Texas Health Science Center , San Antonio , TX , USA.
Anamika
A
Yadav
c Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute , Austin , TX , USA.
Dawit
D
Kidane
d Division of Nephrology and Cancer Center, University of California at Davis , Davis , CA , USA.
Robert H
RH
Weiss
a Department of Cellular and Structural Biology , University of Texas Health Science Center , San Antonio , TX , USA.
Sitai
S
Liang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D012265:Ribonucleotides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D012265:Ribonucleotides; C540162:Rptor protein, mouse; C525637:rictor protein, mouse; D000620:Aminoimidazole Carboxamide; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C031143:AICA ribonucleotide; D005947:Glucose
AICAR; AMPK; Nrf2; OGG1; diabetes; mTOR