Role of Circulating suPAR in FSGS Focal Segmental Glomerulosclerosis (FSGS) is a severe glomerular disease that is characterized by podocyte injury, proteinuria and progressive renal decline, the disease is likely to recur after transplantation in 30% of adults and even in higher number in children. Recently, soluble urokinase plasminogen activator receptor (suPAR) has been found to be elevated in the serum of the majority of patients with FSGS. Animal experiments suggested that suPAR caused podocyte injury and FSGS-type changes in rodents through activation of podocyte beta 3 integrin. As suPAR levels are increased due to variables, such as cancer or infection;and do not routinely present with proteinuria, this proposal seeks to define the precise form (s) of suPAR that is/are acting as a causative factor for focal segmental glomerulosclerosis (FSGS). We hypothesize that diverse effects of suPAR in different diseases are due to different forms of suPAR. Under this grant application we test hypothesis that only the specific form(s) of suPAR, i.e. hypoglycosylated form(s), is (are) responsible for FSGS.
Aim 1 will identify pathological form(s) of suPAR in FSGS patients.
Aim 2 will test pathological suPAR in mice.
Aim 3 will be aimed to develop a more specific ELISA test and Aim 4 will assess the risk of a common genetic variant (P1A2) in the beta 3 gene that might allow integrin hyperactivation in podocytes. In sum, this research program will potentially unravel a major cause of FSGS and might lead to a refined treatment for patients with the disease.
The goal of this grant proposal is to understand the pathogenesis of Focal and Segmental Glomerulosclerosis (FSGS). If our hypothesis is correct, the identification of kidney-pathogenic forms of the soluble urokinase plasminogen activator receptor suPAR will allow for improved risk stratification of patients affected with the disease. I will also allow for novel therapies that treat a root cause of native and post-transplant FSGS and reduce the burden of renal disease for our fellow humans.
|Tian, Xuefei; Kim, Jin Ju; Monkley, Susan M et al. (2014) Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance. J Clin Invest 124:1098-113|
|Trachtman, Howard; Reiser, Jochen (2014) suPAR is the circulating factor in some but not all FSGS. Nat Rev Nephrol 10:610|
|Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto et al. (2014) Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 25:1415-29|
|Delville, Marianne; Sigdel, Tara K; Wei, Changli et al. (2014) A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 6:256ra136|
|Reiser, Jochen; Nast, Cynthia C; Alachkar, Nada (2014) Permeability factors in focal and segmental glomerulosclerosis. Adv Chronic Kidney Dis 21:417-21|
|Reiser, Jochen; Sever, Sanja; Faul, Christian (2014) Signal transduction in podocytes--spotlight on receptor tyrosine kinases. Nat Rev Nephrol 10:104-15|