Soluble Urokinase Receptor and the Kidney Response in Diabetes Mellitus

Figure 1

Schematic depiction of uPAR/suPAR-αvβ3 integrin signaling at the glomerular filtration level in health and diabetic disease. In resting podocytes, uPAR interacts with uPA and anchored to the outer plasma membrane with GPI. This complex is connected to αvβ3 integrin through vitronectin, a β3 integrin ligand. This leads to the initiation of “outside-in” signaling events, which requires the recruitment of linker proteins (paxillin, talin, and vinculin) by integrins for actin involvement. This signaling pathway is responsible for proper actin cytoskeleton assembly, lamellipodia formation, growth, proliferation, differentiation, and cell survival. ECM proteins such as fibronectin, collagen, and laminin are also involved in many cellular activities including ECM organization, cell adhesion and migration. Three homologous domains of uPAR are denoted by D1, D2, and D3, respectively (left panel). In the hyperglycemic state, αvβ3 integrin activity increases causing altered adhesion, migration, and proliferation. These intracellular changes might initiate an “inside-out” signaling affecting integrin’s binding affinity. Soluble uPAR also increases in circulation and probably contributes to the pathology of the diabetic kidney disease, which can be characterized as impaired cytoskeletal organization and podocyte FP effacement. The pathogenic suPAR is mainly generated by bone marrow-immature myeloid cells. Podocyte-specific expression of SMPDL-3b, which is elevated during the course of diabetic kidney disease, prevents αvβ3 integrin activation by interacting with suPAR. This eventually increases RhoA activity and podocyte susceptibility to apoptosis. αvβ3 integrin receptors are also expressed in glomerular endothelium and exposure of endothelial cells to hyperglycemia leads to pathologic outcomes in these cells such as endothelial permeability, migration, and proliferation in response to the ligand occupancy of αvβ3 and concomitant stimulation of IGF-1 (middle panel). Targeting uPAR and suPAR with an uPAR-specific monoclonal antibody can attenuate the adverse effects of uPAR/suPAR-dependent integrin signaling. Using antibodies that bind preferentially to the activated and/or ligand-occupied forms of β3 integrin and β3 integrin small molecule inhibitor, cycloRGDfV, offer alternative ways to disentangle its interactions with uPAR/suPAR. Blocking the ligand occupancy of αvβ3 inhibits the pathogenic mechanisms stimulated by IGF-1 (right panel).