title: Role of podocyte B7-1 in diabetic nephropathy.
abstract: Podocyte injury and resulting albuminuria are hallmarks of diabetic nephropathy, but targeted therapies to halt or prevent these complications are currently not available. Here, we show that the immune-related molecule B7-1/CD80 is a critical mediator of podocyte injury in type 2 diabetic nephropathy. We report the induction of podocyte B7-1 in kidney biopsy specimens from patients with type 2 diabetes. Genetic and epidemiologic studies revealed the association of two single nucleotide polymorphisms at the B7-1 gene with diabetic nephropathy. Furthermore, increased levels of the soluble isoform of the B7-1 ligand CD28 correlated with the progression to ESRD in individuals with type 2 diabetes. In vitro, high glucose conditions prompted the phosphatidylinositol 3 kinase-dependent upregulation of B7-1 in podocytes, and the ectopic expression of B7-1 in podocytes increased apoptosis and induced disruption of the cytoskeleton that were reversed by the B7-1 inhibitor CTLA4-Ig. Podocyte expression of B7-1 was also induced in vivo in two murine models of diabetic nephropathy, and treatment with CTLA4-Ig prevented increased urinary albumin excretion and improved kidney pathology in these animals. Taken together, these results identify B7-1 inhibition as a potential therapeutic strategy for the prevention or treatment of diabetic nephropathy.
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine, San Raffaele Scientific Institute, Milan, Italy; paolo.fiorina@childrens.harvard.edu.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine, San Raffaele Scientific Institute, Milan, Italy; DiSTeBA, Universita' del Salento, Lecce, Italy;
authors.forename: Roberto
authors.initials: R
authors.lastname: Bassi
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Monika A
authors.initials: MA
authors.lastname: Niewczas
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois;
authors.forename: Mehmet M
authors.initials: MM
authors.lastname: Altintas
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Marcus G
authors.initials: MG
authors.lastname: Pezzolesi
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Melissa
authors.initials: M
authors.lastname: Chin
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Sara
authors.initials: S
authors.lastname: Tezza
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Moufida
authors.initials: M
authors.lastname: Ben Nasr
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy;
authors.forename: Deborah
authors.initials: D
authors.lastname: Mattinzoli
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy;
authors.forename: Masami
authors.initials: M
authors.lastname: Ikehata
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy;
authors.forename: Domenico
authors.initials: D
authors.lastname: Corradi
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Valerie
authors.initials: V
authors.lastname: Schumacher
authors.affiliation: Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts;
authors.forename: Lisa
authors.initials: L
authors.lastname: Buvall
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;
authors.forename: Chih-Chuan
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;
authors.forename: Jer-Ming
authors.initials: JM
authors.lastname: Chang
authors.affiliation: Pathology Department, Ospedale di Circolo, Varese, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
authors.affiliation: Pathology Department, Ospedale di Circolo, Varese, Italy;
authors.forename: Giovanna
authors.initials: G
authors.lastname: Finzi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy;
authors.forename: Anna
authors.initials: A
authors.lastname: Solini
authors.affiliation: Kidney Transplant Service, University of San Francisco, San Francisco, California;
authors.forename: Flavio
authors.initials: F
authors.lastname: Vincenti
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy;
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois;
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts;
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
authors.affiliation: Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts;
authors.forename: Peter H
authors.initials: PH
authors.lastname: Mundel
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital, Boston, Massachusetts; and American University of Beirut, Beirut, Lebanon.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018122:B7-1 Antigen / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D050199:Podocytes; D015854:Up-Regulation
chemical_list: D018122:B7-1 Antigen