The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

Abstract

Previously, we showed that some podocytes in juvenile mice are recruited from cells lining Bowman's capsule, suggesting that parietal epithelial cells (PECs) are a progenitor cell population for podocytes. To investigate whether PECs also replenish podocytes in adult mice, PECs were genetically labeled in an irreversible fashion in 5-week-old mice. No significant increase in labeled podocytes was observed, even after 18 months. To accelerate a potential regenerative mechanism, progressive glomerular hypertrophy was induced by progressive partial nephrectomies. Again, no significant podocyte replenishment was observed. Rather, labeled PECs exclusively invaded segments of the tuft affected by glomerulosclerosis, consistent with our previous findings. We next reassessed PEC recruitment in juvenile mice using a different reporter mouse and confirmed significant recruitment of labeled PECs onto the glomerular tuft. Moreover, some labeled cells on Bowman's capsule expressed podocyte markers, and cells on Bowman's capsule were also directly labeled in juvenile podocyte-specific Pod-rtTA transgenic mice. In 6-week-old mice, however, cells on Bowman's capsule no longer expressed podocyte-specific markers. Similarly, in human kidneys, some cells on Bowman's capsule expressed the podocyte marker synaptopodin from 2 weeks to 2 years of age but not at 7 years of age. In summary, podocyte regeneration from PECs could not be detected in aging mice or models of glomerular hypertrophy. We propose that a small fraction of committed podocytes reside on Bowman's capsule close to the vascular stalk and are recruited onto the glomerular tuft during infancy to adolescence in mice and humans.

Unraveling the Role of Podocyte Turnover in Glomerular Aging and Injury

“…We therefore examined the UNx model in which we could not detect, at least in our experimental set-up, any podocyte turnover, a finding that confirms the work of others. 28 These results confirm that glomerular and podocyte hypertrophy is the main adaptation mechanism, which is in line with previous reports. 23,29 Although signaling pathways such as mammalian target of rapamycin that efficiently increase podocyte size have been identified, 5,30,31 the lack of podocyte turnover in response to nephron loss makes these enlarged podocytes the obvious Achilles heel in progressive kidney diseases.…”

Podocyte Number in Children and Adults

“…59,65 Wanner et al 66 recently showed that podocyte generation is mainly active during glomerular development and may occur after acute glomerular injury but was not observed in aging kidneys or in response to nephron loss. Interestingly, a recent study by Berger et al 67 showed that parietal podocytes (PECs expressing podocyte markers) disappeared from Bowman's capsule as glomeruli gradually underwent physiologic hypertrophy, suggesting that there is a functional podocyte reserve that directly differentiates into podocytes on Bowman's capsule. Berger et al 68 proposed that this is explained by the lack of space to accommodate podocytes on the small glomerular tuft of a young child.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Stress and loss of podocytes is likely one of the major determinants of progressive glomerular injury and glomerulosclerosis given their unique anatomical position and terminal differentiation with virtually no regenerative capability (98,99). Pathways contributing to podocyte injury and glomerulosclerosis (100) amongst others include the epidermal growth factor receptor (EGFR) (90), mTOR (101)(102)(103), angiotensin II (104), miR-193a (105), KLF-4 (106), adiponectin (107), RAP1GAP (82), or Rho-A (108).…”