Structural Plasticity of Aged Podocytes Revealed by Volume Electron Microscopy

KEY POINTS: Volume electron microscopy enabled the complete 3D reconstruction of podocytes. Structural changes in podocytes of aged rats were precisely analyzed, and a catalog of these changes was compiled. The structural plasticity contributing to the maintenance of glomerular epithelium by aged podocytes has been elucidated. BACKGROUND: Podocytes are specialized epithelial cells that constitute the glomerular filtration barrier. Because adult kidneys lack podocyte stem cells, the cells produced during development must persist throughout life. However, podocyte numbers decline with aging and disease, suggesting that surviving podocytes may undergo structural adaptations to maintain the glomerular epithelium. The nature of these changes, however, remains poorly understood. METHODS: We used volume electron microscopy to analyze and compare the three-dimensional ultrastructure of podocytes in young adult (1.5-month-old), adult (6-month-old), and aged (24-month-old) male Wistar rats. RESULTS: Aged podocytes exhibited eight characteristic structural alterations: hypertrophy, pseudocystic changes, irregularity of foot processes, fragmentation, pruning of foot processes, autocellular interdigitation, release of lysoendosomal and multivesicular body contents, and an increase in lysosomal volume. Among these, hypertrophy was particularly notable-it resulted in an approximately 4.6-fold increase in podocyte volume and a 3.0-fold increase in total surface area, enabling adequate coverage of the enlarging glomerular surface. Furthermore, in areas where portions of podocytes seemed to be lost because of fragmentation, adjacent podocytes formed de novo autocellular junctions/interdigitation, thereby preventing exposure of the basement membrane. In addition, aged podocytes showed clustering of lysoendosomes and multivesicular bodies, with evidence of their exocytotic release into the urinary space. This process may compensate for the reduced intracellular degradation capacity associated with aging. CONCLUSIONS: Our study demonstrated the remarkable plasticity of podocytes during aging.