^{Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts;}

^{Department of Medicine, Rush University Medical Center, Chicago, Illinois;}

^{Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy;}

^{Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy;}

^{Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts;}

^{Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;}

^{Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;}

^{Pathology Department, Ospedale di Circolo, Varese, Italy;}

^{Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy;}

^{Kidney Transplant Service, University of San Francisco, San Francisco, California;}

^{Transplantation Research Center, Brigham and Women's Hospital, Boston, Massachusetts; and}

^{American University of Beirut, Beirut, Lebanon}

^{Corresponding author.}

Correspondence: Dr. Paolo Fiorina, Division of Nephrology, Boston Children’s Hospital-Harvard Medical School, 300 Longwood Avenue, Enders Building, Fifth Floor, Room En511, Boston, MA 02115. Email: ude.dravrah.snerdlihc@aniroif.oloap

P.F., A.V., and R.B. contributed equally to this work.

Received 2013 May 21; Accepted 2013 Nov 19.

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.

Abstract

Type 2 diabetes (T2D) is rapidly becoming the leading cause of ESRD.¹,² Despite much progress and an overall improvement in the treatment of diabetic nephropathy (DN), the development of ESRD remains an epidemic problem.³ Podocyte foot processes, separated by narrow spaces, constitute the final barrier to urinary protein loss by creating the porous membrane slit diaphragm, the integrity of which is essential for retaining proteins during filtration.⁴,⁵ A primary hallmark of DN is the progressive damage and death of glomerular podocytes,¹,⁶–⁹ resulting in the leaking of proteins into the urine.⁴

B7-1 is an immune-related protein found on antigen-presenting cells that interacts with CD28 and CTLA4 on T cells, thus providing positive or negative costimulatory signals necessary for T-cell activation and survival.¹⁰ Induction of podocyte B7-1 is associated with development of proteinuria in human and murine lupus nephritis, in α₃ integrin knockout mice, in nephrin knockout mice, and in mice with LPS-induced proteinuria.⁵ The latter study also reported that podocytes exposed to LPS upregulate B7-1 in vitro and in vivo, thus leading to podocyte abnormalities and proteinuria.⁵ Of note, B7-1 knockout (B7-1^{) mice are protected from LPS-induced albuminuria, suggesting a causal link between podocyte B7-1 expression and proteinuria.}⁵

Abatacept (CTLA4-Ig) is an inhibitor of B7-1 that is currently used to treat autoimmune diseases.¹¹ Here we show that high glucose induces podocyte B7-1 expression, thereby contributing to podocyte morphologic alterations and ultimately to DN, and that B7-1 blockade with CTLA4-Ig can protect podocytes from high glucose–induced injuries. These results suggest that the CD28/B7-1 pathway is relevant to the pathogenesis of T2D DN in humans, and CTLA4-Ig treatment may therefore offer a therapeutic strategy to combat DN. This notion is further supported by our recent findings showing that Abatacept is a therapy for proteinuria in patients with podocyte B7-1–positive FSGS.¹²

DD, disease duration; SBP, systolic BP; DBP, diastolic BP; AU, arbitrary unit.

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Acknowledgments

P.F. is the recipient of a Juvenile Diabetes Research Foundation (JDRF) career development award, an American Society of Nephrology career development award, and an American Diabetes Association (ADA) mentor-based fellowship grant. P.F. is also supported by grants from Boston Children's Hospital (Translational Research Program), the Harvard Stem Cell Institute (Diabetes Program DP-0123-12-00), and the Italian Ministry of Health (RF-2010-2303119, RF-2010-2314794, and RF-FSR-2008-1213704). A.V. is supported by a Associazione Medici Diabetologi (AMD)–Societa' Italiana di Diabetologia (SID) Pasquale di Coste scholarship, as well as a National Institutes of Health (NIH) research training grant to Boston Children's Hospital in Pediatric Nephrology (T32DK007726-28). A.V. conducted this study as partial fulfillment of his PhD program in Molecular Medicine at San Raffaele University (Milan, Italy). R.B. is supported by an ADA mentor-based fellowship grant to P.F and by an American Society of Transplantation/Genentech clinical science fellowship grant. R.B. conducted this study as partial fulfillment of his PhD program in Biology and Biotechnology at Salento University (Lecce, Italy). L.B. is supported by the Swedish Research Council and by the Swedish Governmental Agency for Innovation Systems. P.M. is supported by grants from the NIH (DK57683, {"type":"entrez-nucleotide","attrs":{"text":"DK062472","term_id":"187691618","term_text":"DK062472"}}DK062472, and {"type":"entrez-nucleotide","attrs":{"text":"DK091218","term_id":"187689841","term_text":"DK091218"}}DK091218). J.R. is supported by grants from the NIH ({"type":"entrez-nucleotide","attrs":{"text":"DK073495","term_id":"187395985","term_text":"DK073495"}}DK073495, {"type":"entrez-nucleotide","attrs":{"text":"DK089394","term_id":"187540309","term_text":"DK089394"}}DK089394, {"type":"entrez-nucleotide","attrs":{"text":"DK101350","term_id":"187544934","term_text":"DK101350"}}DK101350) and A.S.K. is supported by grants from the NIH (DK41526, DK58549 and DK77532).

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2013050518/-/DCSupplemental.

Footnotes

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