Rapid podocyte loss in murine models triggers the formation of podocyte-parietal epithelial cell intercellular bridges.

Abstract

Podocytes are highly specialized, terminally differentiated visceral epithelial cells that are critical for the maintenance of the glomerular filtration barrier. In subtypes of glomerulonephritis and focal segmental glomerulosclerosis (FSGS), injured podocytes trigger the activation and proliferation of neighboring parietal epithelial cells (PECs) which line Bowman's capsule. Mechanisms by which injured podocytes trigger the activation of PECs remain poorly understood. In three independent murine models of proliferative glomerulopathy, we observed that rapid podocyte loss triggered the formation of novel intercellular bridges (or tunneling nanotubes) extending between podocytes and PECs. Immunofluorescence staining of a coculture of mouse podocytes and PECs also revealed the presence of vesicle-like structures within intercellular bridges. In addition, these vesicle-like structures stained positive for Ras-related protein Rab-11A (RAB11A), a RabGTPase involved in the regulation of vesicle transport, and cytoplasmic dynein 1 heavy chain 1, a critical motor protein involved in cargo transport. Finally, we identified intercellular bridges in human kidney biopsies with subtypes of glomerulonephritis and collapsing FSGS, suggesting relevance to human disease.To date, this is the first study to demonstrate that intercellular bridges form between podocytes and parietal epithelial cells in the setting of rapid podocyte loss in subtypes of glomerulonephritis and FSGS.