Multiple Targets for Novel Therapy of FSGS Associated with Circulating Permeability Factor

Figure 3

Scheme showing potential targets for therapy in glomerular injury caused by circulating factor or cytokine. The left panel shows the milieu that favors podocyte dysfunction and proteinuria. Excess activity of an injurious factor or cytokine permits its interaction with receptors on podocytes which, in turn, activates signaling via JAK2/STAT3 and other pathways. Actin cytoskeleton becomes disordered and podocyte architecture and function is altered. The right panel shows some potential treatment goals including the following: (1) decrease factor synthesis or remove it by plasmapheresis, immunoadsorption or other extracorporeal methods; (2a) administer blocker such as galactose or (2b) receptor blocker such as antibody to specific component or receptor; (3) inhibit intracellular signaling by JAK or STAT inhibitor or inhibitor of other essential cell pathways; (4) protect actin cytoskeleton by calcineurin inhibitors such as CsA or by a sphingomyelinase inhibitor such as rituximab. Identification of multiple targets will permit concurrent use of several modalities that may increase effectiveness while limiting side effects.