B7-1/CD80 is known as a bidirectional regulator of T cell activation and tolerance. We previously reported an unanticipated novel role for B7-1 in podocytes as inducible mediator of podocyte injury and proteinuria in humans and animals. B7-1 can be targeted by blocking antibodies such as Abatacept (CTLA4-Ig), which is currently used for the treatment of patients with rheumatoid arthritis. Our novel data obtained with this grant suggest that the anti-proteinuric action of CTLA4-Ig is independent of its inhibitory action on T cell costimulation but stems from a direct effect on podocytes. Our novel data further suggest that the upregulation of B7-1 in podocytes actively contributes to the pathogenesis of proteinuria by altering podocyte structure and function. Most importantly, they offer a rationale for the use o Abatacept as anti-proteinuric treatment. Here we propose to test our central hypothesis that induction of B7-1 expression in podocytes contributes to the pathogenesis of proteinuria by blocking talin mediated ?1 integrin activation in podocytes. We further hypothesize that Abatacept/CTLA4-Ig and possible Belatacept prevent proteinuria by blocking B7-1 signaling in podocytes. To test this hypothesis we propose two Specific Aims.
The first Aim will define the mechanistic role of B7-1 and the effects of its blockade on podocyte- matrix adhesion.
Specific Aim 2 will assess the anti-proteinuric therapeutic potential of B7-1 blockade in mice. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will firmly establish the rationale for a prospective clinical study of B7-1 blockade in patients with proteinuria, including cases of recurrent and non-recurrent FSGS. This should in the long-term enable us to develop novel therapies that tackle proteinuria and glomerulosclerosis by blocking B7-1 signaling in podocytes.

Public Health Relevance

Our work funded by this grant has provided novel insights into the pathogenesis and treatment of proteinuria. It led to the novel concept that B7-1 signaling in podocytes contributes to the pathogenesis of proteinuria by altering podocyte integrin signaling. The work proposed here should provide insight into the molecular mechanism whereby B7-1 expression in podocytes causes proteinuria. It should also establish the molecular rationale for the use of B7-1 blockade as anti-proteinuric therapy in patients with Rituximab-resistant recurrent FSGS and other proteinuric kidney diseases.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Mullins, Christopher V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto et al. (2014) Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 25:1415-29
Brouwers, Olaf; Niessen, Petra M G; Miyata, Toshio et al. (2014) Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes. Diabetologia 57:224-35
Kampe, Kapil; Sieber, Jonas; Orellana, Jana Marina et al. (2014) Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2. Am J Physiol Renal Physiol 306:F401-9
Balbas, Minna D; Burgess, Michael R; Murali, Rajmohan et al. (2014) MAGI-2 scaffold protein is critical for kidney barrier function. Proc Natl Acad Sci U S A 111:14876-81
Sieber, Jonas; Weins, Astrid; Kampe, Kapil et al. (2013) Susceptibility of podocytes to palmitic acid is regulated by stearoyl-CoA desaturases 1 and 2. Am J Pathol 183:735-44
Gurkan, Sevgi; Cabinian, Allison; Lopez, Victoria et al. (2013) Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria. J Pathol 231:248-56
Yu, Chih-Chuan; Fornoni, Alessia; Weins, Astrid et al. (2013) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 369:2416-23
Greka, Anna; Mundel, Peter (2012) Cell biology and pathology of podocytes. Annu Rev Physiol 74:299-323
Wong, Jenny S; Iorns, Elizabeth; Rheault, Michelle N et al. (2012) Rescue of tropomyosin deficiency in Drosophila and human cancer cells by synaptopodin reveals a role of tropomyosin ? in RhoA stabilization. EMBO J 31:1028-40
Greka, Anna; Mundel, Peter (2011) Balancing calcium signals through TRPC5 and TRPC6 in podocytes. J Am Soc Nephrol 22:1969-80

Showing the most recent 10 out of 25 publications