Soluble Urokinase Receptors in Focal Segmental Glomerulosclerosis: A Review on the Scientific Point of View

Abstract

Focal segmental glomerulosclerosis (FSGS) is one of the primary glomerular disorders in both children and adults which can progress to end-stage renal failure. Although there are genetic and secondary causes, circulating factors have also been regarded as an important factor in the pathogenesis of FSGS, because about 40% of the patients with FSGS have recurrence after renal transplantation. Soluble urokinase-type plasminogen activator receptor (suPAR) is a soluble form of uPAR, which is a membrane-bound protein linked to GPI in various immunologically active cells, including podocytes. It has recently been suggested as a potential circulating factor in FSGS by in vitro podocyte experiments, in vivo mice models, and human studies. However, there have also been controversies on this issue, because subsequent studies showed conflicting results. suPAR levels were also increased in patients with other glomerular diseases and were inversely correlated with estimated glomerular filtration rate. Nevertheless, there has been no balanced review on this issue. In this review, we compare the conflicting data on the involvement of suPAR in the pathogenesis of FSGS and shed light on interpretation by taking into account many points and the potential variables and confounders influencing serum suPAR levels.

Figure 1

A hypothesis for the pathogenesis of suPAR-mediated FSGS. suPAR is formed from various immune cells after cleavage of GPI anchor by cytokines such as TNF-α. suPAR can activate αvβ ₃ integrin of podocytes. TNF-α can directly activate podocyte αvβ ₃ integrin and vinculin. Another serum factors might decrease SMPDL3b in podocytes, causing αvβ ₃ integrin activation through increased binding of suPAR/uPAR and αvβ ₃ integrin. Cdc42 and Rac1 can be activated by uPAR-αvβ ₃ integrin signaling and the podocyte actin cytoskeleton shifts from a stationary to a motile phenotype, thereby causing foot process effacement and proteinuria. uPAR-αvβ ₃ integrin signaling in podocytes can be blocked through various pathways. NK, natural killer; uPAR, urokinase-type plasminogen activator receptor; suPAR, soluble urokinase-type plasminogen activator receptor; GPI, glycosylphosphatidylinositol; TNF, tumor necrosis factor; NFAT, nuclear factor of activated T cells; MMF, mycophenolate mofetil; GTP, guanosine-5′-triphosphate; SMPDL, sphingomyelin phosphodiesterase acid-like; ASMase, acid sphingomyelinase.