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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Moxey-Mims, Marva M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rush University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Hayek, Salim S; Ko, Yi-An; Awad, Mosaab et al. (2017) Cardiovascular Disease Biomarkers and suPAR in Predicting Decline in Renal Function: A Prospective Cohort Study. Kidney Int Rep 2:425-432
Dande, Ranadheer R; Peev, Vasil; Altintas, Mehmet M et al. (2017) Soluble Urokinase Receptor and the Kidney Response in Diabetes Mellitus. J Diabetes Res 2017:3232848
Hahm, Eunsil; Wei, Changli; Fernandez, Isabel et al. (2017) Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 23:100-106
Alasfar, Sami; Matar, Dany; Montgomery, Robert A et al. (2017) Rituximab and Therapeutic Plasma Exchange in Recurrent Focal Segmental Glomerulosclerosis Postkidney Transplantation. Transplantation :
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
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
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
Kobayashi, Namiko; Ueno, Toshiharu; Ohashi, Kumi et al. (2015) Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated ?1-integrin endocytosis. Am J Physiol Renal Physiol 308:F614-26
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
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

Showing the most recent 10 out of 23 publications