Role of podocyte B7-1 in diabetic nephropathy

Paolo Fiorina, Andrea Vergani, Roberto Bassi, Monika A. Niewczas, Mehmet M. Altintas, Marcus G. Pezzolesi, Francesca D'Addio, Melissa Chin, Sara Tezza, Moufida Ben Nasr, Deborah Mattinzoli, Masami Ikehata, Domenico Corradi, Valerie Schumacher, Lisa Buvall, Chih Chuan Yu, Jer Ming Chang, Stefano La Rosa, Giovanna Finzi, Anna SoliniFlavio Vincenti, Maria Pia Rastaldi, Jochen Reiser, Andrzej S. Krolewski, Peter H. Mundel, Mohamed H. Sayegh

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1415-1429
Number of pages15
JournalJournal of the American Society of Nephrology
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 1 2014

ASJC Scopus subject areas

  • Nephrology
  • Medicine(all)

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  • Cite this

    Fiorina, P., Vergani, A., Bassi, R., Niewczas, M. A., Altintas, M. M., Pezzolesi, M. G., D'Addio, F., Chin, M., Tezza, S., Nasr, M. B., Mattinzoli, D., Ikehata, M., Corradi, D., Schumacher, V., Buvall, L., Yu, C. C., Chang, J. M., La Rosa, S., Finzi, G., ... Sayegh, M. H. (2014). Role of podocyte B7-1 in diabetic nephropathy. Journal of the American Society of Nephrology, 25(7), 1415-1429. https://doi.org/10.1681/ASN.2013050518