The native human glomerulus features a slit diaphragm resembling a densely interwoven fishnet

The slit diaphragm (SD), a core element of the glomerular filtration barrier, is essential for renal filtration and disrupted in all forms of glomerulopathy. Using cryo-electron tomography of human kidney tissue, we resolved the near-native SD architecture at unprecedented resolution. The SD comprises crisscrossing strands intersecting at ~90 degrees, forming a fishnet-like lattice across the ~44 nm space between podocyte foot processes. An atomic model based on the Nephrin-Neph1 heterodimer reveals ~9 nm spacing in humans, compared with 12.3 nm in mice and 15 nm in Drosophila. Our data establish the SD as a conserved fishnet-like assembly from invertebrates to mammals, with the tighter human lattice likely conferring enhanced permselectivity.