Towards an integrative structural model of the fishnet slit diaphragm: Understanding its physiology through proteomics and structural insight

The kidney slit diaphragm (SD) connects the foot processes of glomerular podocytes, anatomically forming the outermost part of the three-layered glomerular filtration barrier. The SD is a large molecular polymer that, together with the foot processes, covers the glomerular capillaries and has diverse functions. It establishes a strong yet flexible cell-cell contact between foot processes from neighboring podocytes and additionally acts as a dynamic signaling platform linking structural integrity with cellular responses. Understanding the physiology of the SD has been hampered by limited structural insights and a lack of precise knowledge of protein composition of its building blocks.The recent convergence of the proteomic analyses of the SD with atomically resolved structures and in situ cryo-electron tomography imaging have led to the fishnet SD. The fishnet SD is based on the high-resolution 3D cryo-electron tomographic images of native glomeruli that revealed an unexpected fishnet architecture, observed in mouse, fly and human. This breakthrough has provided a new and markedly different view of how we understand and analyze the SD. It provides important principles for understanding spatial self-organization, assembly, turnover, and force compensation and offers an important basis for functional investigations, including the elucidation of molecular mechanisms of clinically relevant diseases.