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.
|Autori interni:||SOLINI, ANNA|
|Autori:||Fiorina P; Vergani A; Bassi R; Niewczas MA; Altintas MM; Pezzolesi MG; D'Addio F; Chin M; Tezza S; Ben Nasr M; Mattinzoli D; Ikehata M; Corradi D; Schumacher V; Buvall L; Yu CC; Chang JM; La Rosa S; Finzi G; Solini A; Vincenti F; Rastaldi MP; Reiser J; Krolewski AS; Mundel PH; Sayegh MH|
|Titolo:||Role of Podocyte B7-1 in Diabetic Nephropathy.|
|Anno del prodotto:||2014|
|Digital Object Identifier (DOI):||10.1681/ASN.2013050518|
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