Role of dynamin, synaptojanin, and endophilin in podocyte foot processes
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
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
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Research Article

Role of dynamin, synaptojanin, and endophilin in podocyte foot processes

Abstract

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.

Authors

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

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Figure 2

Podocyte foot process effacement in pod-Dnm-DKO mice.

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Podocyte foot process effacement in pod-Dnm-DKO mice. (A) Electron mic...
(A) Electron micrographs illustrating the ultrastructure of glomerular capillaries of control and pod-Dnm-DKO mice. In pod-Dnm-DKO capillaries, podocyte foot processes had a nearly normal morphology at P4, but were effaced at 4 weeks. Scale bars: 500 nm. Boxed regions illustrate effaced pod-Dnm-DKO podocyte foot processes at 4 weeks compared with control. (B) High-magnification micrographs from control and mutant glomeruli showing endocytic clathrin-coated pits at 4 weeks of age. Scale bars: 500 nm.