title: Diet-Induced Podocyte Dysfunction in Drosophila and Mammals.
abstract: Diabetic nephropathy is a major cause of end-stage kidney disease. Characterized by progressive microvascular disease, most efforts have focused on injury to the glomerular endothelium. Recent work has suggested a role for the podocyte, a highly specialized component of the glomerular filtration barrier. Here, we demonstrate that the Drosophila nephrocyte, a cell analogous to the mammalian podocyte, displays defects that phenocopy aspects of diabetic nephropathy in animals fed chronic high dietary sucrose. Through functional studies, we identify an OGT-Polycomb-Knot-Sns pathway that links dietary sucrose to loss of the Nephrin ortholog Sns. Reducing OGT through genetic or drug means is sufficient to rescue loss of Sns, leading to overall extension of lifespan. We demonstrate upregulation of the Knot ortholog EBF2 in glomeruli of human diabetic nephropathy patients and a mouse ob/ob diabetes model. Furthermore, we demonstrate rescue of Nephrin expression and cell viability in ebf2(-/-) primary podocytes cultured in high glucose.
authors.affiliation: Department of Developmental and Regenerative Biology and School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029-1020, USA.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Na
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 405B Clinical Research Building, Philadelphia, PA 19104-4539, USA.
authors.forename: Mariya T
authors.initials: MT
authors.lastname: Sweetwyne
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 405B Clinical Research Building, Philadelphia, PA 19104-4539, USA.
authors.forename: Ae Seo Deok
authors.initials: AS
authors.lastname: Park
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 405B Clinical Research Building, Philadelphia, PA 19104-4539, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Susztak
authors.affiliation: Department of Developmental and Regenerative Biology and School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029-1020, USA. Electronic address: ross.cagan@mssm.edu.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Cagan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004040:Dietary Carbohydrates / Q000009:adverse effects; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D013395:Sucrose / Q000633:toxicity
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004040:Dietary Carbohydrates; D029721:Drosophila Proteins; D007136:Immunoglobulins; D008565:Membrane Proteins; D017351:N-Acetylglucosaminyltransferases; D013395:Sucrose; C410904:SNS protein, Drosophila; C113267:nephrin; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase