Figure 9. Increased podocyte expression of RAP1GAP drives podocyte injury by preventing activation of β1 integrin.
In normal podocytes, several upstream signals, including RAP1GAP, converge to maintain proper cellular RAP1 homeostasis and appropriate β1 integrin–mediated adhesion and signaling. In FSGS, however, increased podocyte expression of RAP1GAP leads to inhibition of RAP1-GTPase and relative accumulation of RAP1 as RAP1-GDP. This leads to a reduction in activated β1 integrin, including reduced adhesion to GBM components. We propose that this pathway is an important mediator of podocyte detachment from the GBM, a process characteristic of podocyte loss in human glomerular diseases such as FSGS. Images shown are from a control and a podocyte-specific Rap1-haploinsufficient mouse (original magnification, ×600).