Primary focal and segmental glomerulosclerosis and soluble factor urokinase-type plasminogen activator receptor

Abstract

Primary focal and segmental glomerulosclerosis (FSGS) may be due to genetic or acquired etiologies and is a common cause of nephrotic syndrome with high morbidity that often leads to end-stage renal failure. The different available therapeutic approaches are unsuccessful, in part due to partially deciphered heterogeneous and complex pathophysiological mechanisms. Moreover, the term FSGS, even in its primary form, comprises a histological description shared by a number of different causes with completely different molecular pathways of disease. This review focuses on the latest developments regarding the pathophysiology of primary acquired FSGS caused by soluble factor urokinase type plasminogen activator receptor, a circulating permeability factor involved in proteinuria and edema formation, and describes recent advances with potential success in therapy.

Keywords: Plasmin; Podocyte; Primary acquired focal and segmental glomerulosclerosis; Proteinuria; Soluble factor urokinase type plasminogen activator receptor.

Figure 1

Differences in urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and soluble urokinase plasminogen activator receptor (modified from reference number 18). D_I: Domain 1; D_II: Domain 2; D_III: Domain 3. uPA: Urokinase-type plasminogen activator; suPAR: Soluble urokinase plasminogen activator receptor.

Figure 2

Potential pharmacological strategies in primary acquired focal and segmental glomerulosclerosis. Potential strategies. 1: Inhibition of soluble urokinase plasminogen activator receptor (suPAR) or other permeability factors secretion onto circulation or a decrease in the pool of suPAR secreting cells (immunosuppression); 2: suPAR or other permeability factors removal from the circulation (plasmapheresis, immunoadsorption); 3: Inhibition of uPAR activation; 4: Plasmin antagonists 5: Stabilization of podocyte and slit diaphragm proteins (immunosuppression, angiotensin converting enzyme inhibitors, angiotensin receptor blockers); 6: Endothelial protectors; 7: Plasmin-integrin coupling inhibitors (monoclonal antibodies, amiloride); 8: Plasmin-tubular ENa+C inhibitors (amiloride). GBM: Glomerular basement membrane.