Cryo-electron tomographic analysis of anti-nephrin-mediated podocytopathy

Birtasu, A. N.; Hengel, F. E.; Tomas, N. M.; Wieland, K.; Dehde, S.; Alves, J.; Scheffer, M. P.; Grahammer, F.; Huber, T. B.; Frangakis, A. S.

doi:10.64898/2026.02.26.708131

bioRxiv · 10.64898/2026.02.26.708131

Cryo-electron tomographic analysis of anti-nephrin-mediated podocytopathy

Birtasu, A. N.·Hengel, F. E.·Tomas, N. M.·Wieland, K.·Dehde, S.·Alves, J.·Scheffer, M. P.·Grahammer, F.·Huber, T. B.·Frangakis, A. S.

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Abstract

Nephrotic kidney diseases are characterized by proteinuria caused by dysfunction of the glomerular filtration barrier. Here, we perform an ultrastructural analysis of anti-nephrin-mediated podocytopathy by visualizing the near-native slit diaphragm in situ across defined stages of disease progression using cryo-electron tomography. Our analysis shows that at early disease stages punctuate cell-cell membrane approximations appear, with basal membrane apposition between adjacent podocyte foot processes, while the initially planar, fishnet slit diaphragm progressively bends into a dome-shaped configuration towards the urinary space. At later stages, slit diaphragm disappearance coincides with the appearance of endosomal and vesicular structures and extensive cytoskeletal reorganization. These cryo-electron tomography-based observations provide a structural framework for understanding how antibody binding to nephrin translates into podocyte architectural failure.

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Birtasu, A. N., Hengel, F. E., Tomas, N. M., Wieland, K., Dehde, S., Alves, J., Scheffer, M. P., Grahammer, F., Huber, T. B., Frangakis, A. S.. 2026-02-28. Cryo-electron tomographic analysis of anti-nephrin-mediated podocytopathy. https://doi.org/10.64898/2026.02.26.708131

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