title: Role of O-linked N-acetylglucosamine modification in diabetic nephropathy.
abstract: Increased O-linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) is a known contributor to diabetes; however, its relevance in diabetic nephropathy (DN) is poorly elucidated. Here, we studied the process and enzymes of O-GlcNAcylation with a special emphasis on Akt-endothelial nitric oxide synthase (eNOS) and heat shock protein (HSP)72 signaling. Since tubular injury is the prominent site of DN, the effect of hyperglycemia was first measured in proximal tubular (HK2) cells cultured in high glucose. In vivo O-GlcNAcylation and protein levels of O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), phosphorylated (p)Akt/Akt, peNOS/eNOS, and HSP72 were assessed in the kidney cortex of streptozotocin-induced diabetic rats. The effects of various renin-angiotensin-aldosterone system (RAAS) inhibitors were also evaluated. In proximal tubular cells, hyperglycemia-induced OGT expression led to increased O-GlcNAcylation, which was followed by a compensatory increase of OGA. In parallel, peNOS and pAkt levels decreased, whereas HSP72 increased. In diabetic rats, elevated O-GlcNAcylation was accompanied by decreased OGT and OGA. RAAS inhibitors ameliorated diabetes-induced kidney damage and prevented the elevation of O-GlcNAcylation and the decrement of pAkt, peNOS, and HSP72. In conclusion, hyperglycemia-induced elevation of O-GlcNAcylation contributes to the progression of DN via inhibition of Akt/eNOS phosphorylation and HSP72 induction. RAAS blockers successfully inhibit this process, suggesting a novel pathomechanism of their renoprotective action in the treatment of DN.
authors.affiliation: MTA-SE "Lendulet" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Renata
authors.initials: R
authors.lastname: Gellai
authors.affiliation: MTA-SE "Lendulet" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.|MTA-SE Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Hodrea
authors.affiliation: MTA-SE "Lendulet" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Lenart
authors.affiliation: MTA-SE "Lendulet" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Adam
authors.initials: A
authors.lastname: Hosszu
authors.affiliation: MTA-SE "Lendulet" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Sandor
authors.initials: S
authors.lastname: Koszegi
authors.affiliation: MTA-SE "Lendulet" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Dora
authors.initials: D
authors.lastname: Balogh
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Agota
authors.initials: A
authors.lastname: Ver
authors.affiliation: First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Nora F
authors.initials: NF
authors.lastname: Banki
authors.affiliation: Teaching Hospital Mór Kaposi, Kaposvar, Hungary; and.
authors.forename: Norbert
authors.initials: N
authors.lastname: Fulop
authors.affiliation: MTA-SE "Lendulet" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Agnes
authors.initials: A
authors.lastname: Molnar
authors.affiliation: Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Wagner
authors.affiliation: MTA-SE Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Adam
authors.initials: A
authors.lastname: Vannay
authors.affiliation: MTA-SE Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.|First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Attila J
authors.initials: AJ
authors.lastname: Szabo
authors.affiliation: MTA-SE "Lendulet" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary; fekete.andrea@med.semmelweis-univ.hu.|First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fekete
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004656:Enalapril / Q000494:pharmacology; D006031:Glycosylation; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D050884:HSP72 Heat-Shock Proteins; D004656:Enalapril; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan; D000117:Acetylglucosamine
keywords: O-linked β-N-acetylglucosamine glycosylation; diabetic nephropathy; endothelial nitric oxide synthase; heat shock protein 72; renin-angiotensin-aldosterone system