Alteration of Forkhead Box O (Foxo4) Acetylation Mediates Apoptosis of Podocytes in Diabetes Mellitus 英文参考文献.docVIP

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Alteration of Forkhead Box O (Foxo4) Acetylation Mediates Apoptosis of Podocytes in Diabetes Mellitus 英文参考文献.doc

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Alteration of Forkhead Box O (Foxo4) Acetylation Mediates Apoptosis of Podocytes in Diabetes Mellitus 英文参考文献

AlterationofForkheadBoxO(Foxo4)Acetylation MediatesApoptosisofPodocytesinDiabetesMellitus PeterY.Chuang1*,YanDai1,2,RuijieLiu3,HelenHe1,MatthiasKretzler4,BelindaJim5,ClemensD. Cohen6,JohnC.He1,2 1Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America, 2Department of Nephrology, ShanghaiJiaotongUniversityAffiliatedFirstPeople’sHospital,Shanghai,China,3JamesJ.PetersVAMedicalCenter,Bronx,NewYork,UnitedStatesofAmerica,4Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America, 5Division of Nephrology, Department of Medicine,JacobiMedicalCenter,AlbertEinsteinCollegeofMedicine,Bronx,NewYork,UnitedStatesofAmerica,6DivisionofNephrologyandInstituteofPhysiology, UniversityofZurich,Zurich,Switzerland Abstract Thenumberofkidneypodocytesisreducedindiabeticnephropathy.Advancedglycationendproducts(AGEs)accumulate inpatientswithdiabetesandpromotetheapoptosisofpodocytebyactivatingtheforkheadboxO4(Foxo4)transcription factortoincreasetheexpressionofapro-apoptosisgene,Bcl2l11.Usingchromatinimmunoprecipitationwedemonstrate 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 bindingandtranscriptionofBcl2l11inpodocytestreatedwithAGE-BSA.Theexpressionofaproteindeacetylasethattargets Foxo4fordeacetylation,sirtuin(Sirt1),isdownregulatedinculturedpodocytesbyAGE-BSAtreatmentandinglomeruliof diabeticpatients.SIRT1overexpressioninculturedmurinepodocytespreventsAGE-inducedapoptosis.Glomeruliisolated fromdiabeticdb/dbmicehaveincreasedacetylationofFoxo4,suppressedexpressionofSirt1,andincreasedexpressionof Bcl2l11comparedtonon-diabeticlittermates.Together,ourdataprovideevidencethatalterationofFoxo4acetylationand down regulation of Sirt1 expression in diabetes promote podocyte apoptosis.