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.
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.
|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|
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