The primary function of the kidneys is to filter the blood to remove waste and retain blood cells and proteins. Podocytes (shown in the panels above) are specialized kidney cells that form a filtering structure known as a slit diaphragm. Disruption of the podocytes results in the enlargement of the slit diaphragms, causing nephrotic syndrome and eventual renal failure. Soda et al. identified a protein network in podocytes that is responsible for maintaining the structural integrity of the slit diaphragms. By engineering mice that lack components of this protein network, they blocked the formation of the slit diaphragms in the kidney. Interestingly, they found that this same protein network is highly similar to the networks that mediate the development of synapses in neurons.
Podocytes are specialized cells that play an integral role in the renal glomerular filtration barrier via their foot processes. The foot processes form a highly organized structure, the disruption of which causes nephrotic syndrome. Interestingly, several similarities have been observed between mechanisms that govern podocyte organization and mechanisms that mediate neuronal synapse development. Dynamin, synaptojanin, and endophilin are functional partners in synaptic vesicle recycling via interconnected actions in clathrin-mediated endocytosis and actin dynamics in neurons. A role of dynamin in the maintenance of the kidney filtration barrier via an action on the actin cytoskeleton of podocytes was suggested. Here we used a conditional double-KO of dynamin 1 (Dnm1) and Dnm2 in mouse podocytes to confirm dynamin’s role in podocyte foot process maintenance. In addition, we demonstrated that while synaptojanin 1 (Synj1) KO mice and endophilin 1 (Sh3gl2), endophilin 2 (Sh3gl1), and endophilin 3 (Sh3gl3) triple-KO mice had grossly normal embryonic development, these mutants failed to establish a normal filtration barrier and exhibited severe proteinuria due to abnormal podocyte foot process formation. These results strongly implicate a protein network that functions at the interface between endocytosis and actin at neuronal synapses in the formation and maintenance of the kidney glomerular filtration barrier.
Keita Soda, Daniel M. Balkin, Shawn M. Ferguson, Summer Paradise, Ira Milosevic, Silvia Giovedi, Laura Volpicelli-Daley, Xuefei Tian, Yumei Wu, Hong Ma, Sung Hyun Son, Rena Zheng, Gilbert Moeckel, Ottavio Cremona, Lawrence B. Holzman, Pietro De Camilli, Shuta Ishibe