title: Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus.
abstract: The number of kidney podocytes is reduced in diabetic nephropathy. Advanced glycation end products (AGEs) accumulate in patients with diabetes and promote the apoptosis of podocyte by activating the forkhead box O4 (Foxo4) transcription factor to increase the expression of a pro-apoptosis gene, Bcl2l11. Using chromatin immunoprecipitation we demonstrate that AGE-modified bovine serum albumin (AGE-BSA) enhances Foxo4 binding to a forkhead binding element in the promoter of Bcl2lll. AGE-BSA also increases the acetylation of Foxo4. Lysine acetylation of Foxo4 is required for Foxo4 binding and transcription of Bcl2l11 in podocytes treated with AGE-BSA. The expression of a protein deacetylase that targets Foxo4 for deacetylation, sirtuin (Sirt1), is down regulated in cultured podocytes by AGE-BSA treatment and in glomeruli of diabetic patients. SIRT1 over expression in cultured murine podocytes prevents AGE-induced apoptosis. Glomeruli isolated from diabetic db/db mice have increased acetylation of Foxo4, suppressed expression of Sirt1, and increased expression of Bcl2l11 compared to non-diabetic littermates. Together, our data provide evidence that alteration of Foxo4 acetylation and down regulation of Sirt1 expression in diabetes promote podocyte apoptosis. Strategies to preserve Sirt1 expression or reduce Foxo4 acetylation could be used to prevent podocyte loss in diabetes.
authors.affiliation: Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America. peter.chuang@mssm.edu
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Chuang
authors.forename: Yan
authors.initials: Y
authors.lastname: Dai
authors.forename: Ruijie
authors.initials: R
authors.lastname: Liu
authors.forename: Helen
authors.initials: H
authors.lastname: He
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Belinda
authors.initials: B
authors.lastname: Jim
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: John C
authors.initials: JC
authors.lastname: He
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002417:Cattle; D018797:Cell Cycle Proteins; D002460:Cell Line; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; C525394:FoxO4 protein, mouse; D017127:Glycation End Products, Advanced; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012710:Serum Albumin, Bovine; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1