The current studies used a genetic fate mapping approach to prove that adult podocytes can be partially replenished, following depletion. Inducible NPHS2-rtTA/tetO-Cre/RS-ZsGreen-R reporter mice were generated in order to permanently label podocytes with the ZsGreen reporter. Experimental FSGS was induced with a cytotoxic podocyte antibody. On FSGS d7, immunostaining for the podocyte markers p57, synaptopodin and podocin were markedly decreased by 44%, accompanied by a decrease in ZsGreen fluorescence. The nuclear stain DAPI was absent in segments of reduced ZsGreen and podocyte marker staining, consistent with podocyte depletion. p57, synaptopodin, podocin and DAPI staining increased at FSGS d28, and were augmented by the ACE-inhibitor Enalapril, consistent with a partial replenishment of podocytes. In contrast, ZsGreen-fluorescence did not return and remained significantly low at d28, indicating replenishment was from a non-podocyte origin. Despite BrdU administration thrice weekly throughout the course of disease, BrdU staining was not detected in podocytes, consistent with an absence of proliferation. Although, ZsGreen reporting was reduced in the tuft at FSGS d28, labeled podocytes were detected along Bowman's capsule in a subset of glomeruli, consistent with migration from the tuft. Moreover, more than half of the migrated podocytes co-expressed the parietal epithelial cell (PEC) proteins Claudin-1, SSeCKS and PAX8. These results show that although podocytes can be partially replenished following abrupt depletion, a process augmented by ACE-inhibition, the source(s) are non-podocyte in origin, and are independent of proliferation. Furthermore, a subset of podocytes migrate to Bowman's capsule, and begin to co-express PEC markers.
- glomerular parietal epithelial cells
- Copyright © 2015, American Journal of Physiology - Renal Physiology