title: Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease.
abstract: Diabetic kidney disease (DKD) is the most common cause of ESRD in the United States. Podocyte injury is an important feature of DKD that is likely to be caused by circulating factors other than glucose. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor found to be elevated in the serum of patients with FSGS and causes podocyte αVβ3 integrin-dependent migration in vitro. Furthermore, αVβ3 integrin activation occurs in association with decreased podocyte-specific expression of acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in kidney biopsy specimens from patients with FSGS. However, whether suPAR-dependent αVβ3 integrin activation occurs in diseases other than FSGS and whether there is a direct link between circulating suPAR levels and SMPDL3b expression in podocytes remain to be established. Our data indicate that serum suPAR levels are also elevated in patients with DKD. However, unlike in FSGS, SMPDL3b expression was increased in glomeruli from patients with DKD and DKD sera-treated human podocytes, where it prevented αVβ3 integrin activation by its interaction with suPAR and led to increased RhoA activity, rendering podocytes more susceptible to apoptosis. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in experimental DKD but not FSGS, indicating that SMPDL3b expression levels determined the podocyte injury phenotype. These observations suggest that SMPDL3b may be an important modulator of podocyte function by shifting suPAR-mediated podocyte injury from a migratory phenotype to an apoptotic phenotype and that it represents a novel therapeutic glomerular disease target.
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and Department of Internal Medicine, Division of Nephrology, Yonsei University College of Medicine, Seoul, Korea;
authors.forename: Tae-Hyun
authors.initials: TH
authors.lastname: Yoo
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pedigo
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Johanna
authors.initials: J
authors.lastname: Guzman
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and.
authors.forename: Mayrin
authors.initials: M
authors.lastname: Correa-Medina
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Rush University, Chicago, Illinois;
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Villarreal
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and.
authors.forename: Alla
authors.initials: A
authors.lastname: Mitrofanova
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and.
authors.forename: Farah
authors.initials: F
authors.lastname: Leclercq
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and.
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Rush University, Chicago, Illinois;
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan;
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Diabetes Epidemiology and Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, Phoenix, Arizona;
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland; Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Diabetes and Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland; and.
authors.forename: Markku
authors.initials: M
authors.lastname: Lehto
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland; Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Diabetes and Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland; and.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland; Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Diabetes and Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland; and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Rush University, Chicago, Illinois;
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida;
authors.forename: George William
authors.initials: GW
authors.lastname: Burke
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida; afornoni@med.miami.edu smerscher@med.miami.edu.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida; afornoni@med.miami.edu smerscher@med.miami.edu.
authors.forename: Sandra
authors.initials: S
authors.lastname: Merscher
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000293:injuries / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D050199:Podocytes / Q000166:cytology / Q000473:pathology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D039302:Integrin alphaVbeta3; D016023:Integrins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; C508196:SMPDL3B protein, human; D013108:Sphingomyelin Phosphodiesterase; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C000595964:sphingomyelinase-like phosphodiesterase 3b, mouse; C526380:RhoA protein, mouse; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: FSGS; diabetic nephropathy; glomerular disease; podocyte; proteinuria