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.

Podocytes play a key role in the pathogenesis of glomerular diseases. They exhibit a complex morphology with specialized cellular projections, between which the intercellular contact—the slit diaphragm—is located. This structure is essential for the functional integrity of the glomerular filtration barrier. Neurons also possess highly differentiated cellular extensions, whose development is directed by extracellular “guidance cues” that act through specific neuronal receptors.

Many of these guidance cues are also expressed in podocytes and are involved in the development and disease-associated remodeling of podocyte processes. The neurotrophic receptor tyrosine kinase 3 (Ntrk3) is one such neuronal guidance receptor expressed in podocytes. We have shown that Ntrk3 can transmit signals to the actin cytoskeleton of cultured podocytes via Erk- and WAVE2-dependent pathways (Gromnitza et al., FASEB J, 2018). ). This signaling cascade leads to enhanced podocyte migration.

In this research project, we will investigate the role of Ntrk3 in podocytes in vivo using tissue-specific mouse models and characterize the underlying molecular mechanisms in podocyte culture systems.

(DFG project number 447767934).