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.
|Hayek, Salim S; Sever, Sanja; Ko, Yi-An et al. (2015) Soluble Urokinase Receptor and Chronic Kidney Disease. N Engl J Med 373:1916-25|
|Garin, Eduardo H; Reiser, Jochen; Cara-Fuentes, Gabriel et al. (2015) Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr Nephrol 30:469-77|
|Trachtman, Howard; Vento, Suzanne; Herreshoff, Emily et al. (2015) Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol 16:111|
|Anwar, Siddiq; Larson, Derek S; Naimi, Nima et al. (2015) A case report of adrenocorticotropic hormone to treat recurrent focal segmental glomerular sclerosis post-transplantation and biomarker monitoring. Front Med (Lausanne) 2:13|
|Staeck, Oliver; Slowinski, Torsten; Lieker, Ina et al. (2015) Recurrent Primary Focal Segmental Glomerulosclerosis Managed With Intensified Plasma Exchange and Concomitant Monitoring of Soluble Urokinase-Type Plasminogen Activator Receptor-Mediated Podocyte Î²3-integrin Activation. Transplantation 99:2593-7|
|Yoo, Tae-Hyun; Pedigo, Christopher E; Guzman, Johanna et al. (2015) Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. J Am Soc Nephrol 26:133-47|
|Kopp, Jeffrey B; Winkler, Cheryl A; Zhao, Xiongce et al. (2015) Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial. J Am Soc Nephrol 26:1443-8|
|Lee, Ha Won; Khan, Samia Q; Faridi, Mohd Hafeez et al. (2015) A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules. J Am Soc Nephrol 26:2741-52|
|Wei, Changli; Sigdel, Tara K; Sarwal, Minnie M et al. (2015) Circulating CD40 autoantibody and suPAR synergy drives glomerular injury. Ann Transl Med 3:300|
|Kobayashi, Namiko; Ueno, Toshiharu; Ohashi, Kumi et al. (2015) Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated Î²1-integrin endocytosis. Am J Physiol Renal Physiol 308:F614-26|
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