Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived circulating signaling molecule that has been implicated in chronic kidney disease， such as focal segmental glomerulosclerosis (FSGS). Typically， native uPAR (isoform 1) translates to a 3-domain protein capable of binding and activating integrins， yet the function of additional isoforms generated by alternative splicing is unknown. Here， we characterized mouse uPAR isoform 2 (msuPAR2)， encoding domain I and nearly one-half of domain II， as a dimer in solution， as revealed by 3D electron microscopy structural analysis. In vivo， msuPAR2 transgenic mice exhibited signs of severe renal disease characteristic of FSGS with proteinuria， loss of kidney function， and glomerulosclerosis. Sequencing of the glomerular RNAs from msuPAR2-Tg mice revealed a differentially expressed gene signature that includes upregulation of the suPAR receptor Itgb3， encoding β3 integrin. Crossing msuPAR2-transgenic mice with 3 different integrin β3 deficiency models rescued msuPAR2-mediated kidney function. Further analyses indicated a central role for β3 integrin and c-Src in msuPAR2 signaling and in human FSGS kidney biopsies. Administration of Src inhibitors reduced proteinuria in msuPAR2-transgenic mice. In conclusion， msuPAR2 may play an important role in certain forms of scarring kidney disease.