In most glomerular diseases, disruption of the kidney's filtration function manifests as effacement of podocyte foot processes, which is accompanied by reorganization of the slit diaphragm and the podocyte actin cytoskeleton. The cell adhesion protein nephrin is essential for the proper formation and maintenance of podocyte foot processes and slit diaphragms. Nephrin signals are transmitted from the slit diaphragm via actin cytoskeleton-associated proteins such as Crk1/2 and CrkL, which induce lamellipodia formation in cultured podocytes (George, Verma et al., Journal of Clinical Investigation, 2012; George, Fan, Dlugos, Soofi et al., Kidney International, 2014). Since nephrin activation leads to lamellipodia formation in podocyte culture, we hypothesized that nephrin transmits signals to integrins at focal adhesions. We demonstrated that nephrin activation leads to β-integrin activation in cultured podocytes (Dlugos, Picciotto et al., J Am Soc Nephrol, 2019).

In this project, we aim to dissect the nephrin signaling cascade from intercellular contacts to integrins and its impact on podocyte adhesion at the molecular level. To achieve this, we employ podocyte culture systems, mouse models, and the model organism Drosophila melanogaster, which expresses slit diaphragm proteins—such as the nephrin ortholog Sticks-and-stones—in its nephrocytes.