suPAR in diabetic complications: Establishing a suPAR overexpressing mouse model
Epidemiological studies suggest that elevated soluble urokinase plasminogen activator receptor (suPAR) concentration in plasma and urine are associated with increased risk of cardiovascular diseases (CVD), Type 2 diabetes, and cancer. Although these studies suggest that increased suPAR concentration might predict risk of presenting with these pathologies, suPAR’s role in disease pathogenesis remains unclear. The possibility that suPAR either is causative for or contributes to disease pathogenesis was recently suggested by Wei et al. who reported that administration of suPAR to mice resulted in proteinuria and focal and segmental glomerular histopathology. While these observations require validation, they provide rationale for the hypothesis that chronically increased suPAR might contribute directly to the pathogenesis of diabetic complications including its cardiovascular complications or diabetic nephropathy. Here we propose developing models to test this hypothesis directly by creating and initially characterizing transgenic mouse models in which suPAR protein is over-expressed from liver in an inducible fashion. GPI-linked membrane-associated uPAR undergoes proteolytic cleavage to produce soluble proteolytic products detectable in blood and urine. Because one cannot predict a priori which product is functionally relevant, two mouse models will be created, one expressing suPAR protein containing all three suPAR ectodomains and one expressing only domains II and III. Following validation, these mouse lines will be employed to examine the hypothesis that suPAR induces a FSGS phenotype. They will also be used to test the hypothesis that over-expression of suPAR in mice on a type I diabetic background potentiates the renal phenotype associated with these diabetic mouse models. These mouse lines will be made available to the interested investigative community as soon as validation is complete.

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