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J Am Soc Nephrol. 2014 Jul;25(7):1415-29. doi: 10.1681/ASN.2013050518. Epub 2014 Mar 27.

Role of podocyte B7-1 in diabetic nephropathy.

Author information

1
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.
2
Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine, San Raffaele Scientific Institute, Milan, Italy;
3
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;
4
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts;
5
Department of Medicine, Rush University Medical Center, Chicago, Illinois;
6
Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
7
Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy;
8
Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy;
9
Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts;
10
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;
11
Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;
12
Pathology Department, Ospedale di Circolo, Varese, Italy;
13
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy;
14
Kidney Transplant Service, University of San Francisco, San Francisco, California;
15
Transplantation Research Center, Brigham and Women's Hospital, Boston, Massachusetts; and American University of Beirut, Beirut, Lebanon.

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.

PMID:
24676639
PMCID:
PMC4073425
DOI:
10.1681/ASN.2013050518
[Indexed for MEDLINE]
Free PMC Article

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