Role of Podocyte B7-1 in Diabetic Nephropathy

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 correlatedwiththeprogressiontoESRDinindividualswithtype2diabetes.Invitro,highglucoseconditions promptedthephosphatidylinositol3kinase–dependentupregulationofB7-1inpodocytes,andtheectopic expression of B7-1 in podocytes increased apoptosis and induced disruption of the cytoskeleton that were reversedbytheB7-1inhibitorCTLA4-Ig.PodocyteexpressionofB7-1wasalsoinducedinvivointwomurine 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.