TY - JOUR
T1 - Role of podocyte B7-1 in diabetic nephropathy
AU - Fiorina, Paolo
AU - Vergani, Andrea
AU - Bassi, Roberto
AU - Niewczas, Monika A.
AU - Altintas, Mehmet M.
AU - Pezzolesi, Marcus G.
AU - D'Addio, Francesca
AU - Chin, Melissa
AU - Tezza, Sara
AU - Nasr, Moufida Ben
AU - Mattinzoli, Deborah
AU - Ikehata, Masami
AU - Corradi, Domenico
AU - Schumacher, Valerie
AU - Buvall, Lisa
AU - Yu, Chih Chuan
AU - Chang, Jer Ming
AU - La Rosa, Stefano
AU - Finzi, Giovanna
AU - Solini, Anna
AU - Vincenti, Flavio
AU - Rastaldi, Maria Pia
AU - Reiser, Jochen
AU - Krolewski, Andrzej S.
AU - Mundel, Peter H.
AU - Sayegh, Mohamed H.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2013050518
DO - 10.1681/ASN.2013050518
M3 - Article
C2 - 24676639
AN - SCOPUS:84907188863
VL - 25
SP - 1415
EP - 1429
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 7
ER -