Myofibroblast differentiation: plasma membrane microdomains and cell phenotype

Myofibroblast differentiation characterizes a prominent cellular phenotype identified in experimental models of progressive kidney disease and human kidney biopsies. Mesangial cells, tubulointerstitial fibroblasts and, perhaps, tubular epithelial cells undergo myofibroblast differentiation, a process characterized by alpha-actin expression, synthesis of interstitial collagens and a growth response. Inhibition of myofibroblast differentiation could prevent kidney disease progression but may be difficult to accomplish, since inhibition of multiple signaling pathways would be required. Cell biology advances have enabled a better understanding of how information from many microenvironmental stimuli are integrated by spatial compartmentalization of extracellular receptors and cytosolic signaling molecules within specialized plasma membrane domains, such as focal adhesions and lipid rafts. We review this information and hypothesize that myofibroblast differentiation of renal cells can only proceed if the spatial arrangement of intracellular molecules, in large part determined by extracellular matrix-regulated cytoskeletal organization, permits activation of appropriate signaling pathways by soluble molecules interacting with receptors in specialized plasma membrane microdomains. If proven, this hypothesis suggests targeting key molecules within adhesion complexes and rafts (in some cases with drugs that are already clinically available) may provide more effective therapy for kidney disease progression.