title: Diabetes induces lysine acetylation of intermediary metabolism enzymes in the kidney.
abstract: Cells in which insulin is not required for glucose uptake are susceptible to the long-term complications of diabetes. Even in these tissues, however, the major perturbations that would otherwise be engendered by the greatly increased intracellular glucose concentration are mollified by adaptive changes in the enzymes of intermediary metabolism. These include allosteric regulation, product inhibition, and covalent modification as well as alterations in gene transcription. More recently, advances in proteomic technology have shown that reversible acetylation of the ε-amino group of lysine provides an additional means of modulating protein function and, in particular, enzyme activity. Here, we explored the extent of protein acetylation in an organ susceptible to the long-term complications of diabetes, examining the kidneys of rats with streptozotocin-induced diabetes and kidney cells exposed to high glucose. Using high-resolution mass spectrometry coupled with immunoaffinity enrichment, we identified 47 lysine-acetylated proteins in the kidneys of diabetic rats compared with 11 in control kidneys. Bioinformatic interrogation of the acetylome from diabetic animals showed a predominance of metabolic pathway involvement including the citrate acid cycle, glycolysis/gluconeogenesis, and metabolism of branched chain amino acids. Increased lysine acetylation was also noted in mesangial and tubular cells exposed to 25 mmol/L compared with 5.6 mmol/L glucose. These findings highlight acetylation as a posttranslational modification affecting numerous proteins. Current drug discovery efforts to develop small molecule inhibitors and activators of various lysine acetylases and deacetylases offer a new potential strategy to reduce the likelihood of diabetes complications.
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Hari
authors.initials: H
authors.lastname: Kosanam
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Diamandis
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada richard.gilbert@utoronto.ca.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002952:Citric Acid Cycle; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004798:Enzymes / Q000378:metabolism*; D006019:Glycolysis; D007668:Kidney / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008297:Male; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000032:analysis / Q000378:metabolism; D051381:Rats
chemical_list: D004798:Enzymes; D020543:Proteome; D000123:Acetyltransferases; D008239:Lysine