WT1 Is Necessary for the Proliferation and Migration of Cells of Renin Lineage Following Kidney Podocyte Depletion

Abstract

SummaryWilms' tumor suppressor 1 (WT1) plays an important role in cell proliferation and mesenchymal-epithelial balance in normal development and disease. Here, we show that following podocyte depletion in three experimental models, and in patients with focal segmental glomerulosclerosis (FSGS) and membranous nephropathy, WT1 increased significantly in cells of renin lineage (CoRL). In an animal model of FSGS in RenWt1fl/fl reporter mice with inducible deletion of WT1 in CoRL, CoRL proliferation and migration to the glomerulus was reduced, and glomerular disease was worse compared with wild-type mice. To become podocytes, CoRL undergo mesenchymal-to-epithelial transformation (MET), typified by reduced staining for mesenchymal markers (MYH11, SM22, αSMA) and de novo expression of epithelial markers (E-cadherin and cytokeratin18). Evidence for changes in MET markers was barely detected in RenWt1fl/fl mice. Our results show that following podocyte depletion, WT1 plays essential roles in CoRL proliferation and migration toward an adult podocyte fate.

mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans

“…PECs have also gained attention as potential sources of additional podocytes in the postnatal period (14). Recent publications have shown that podocyte regeneration may be possible in specific scenarios (45)(46)(47)(48)(49)(50)(51), but other publications have ruled this out (10,52). Conflicting evidence may highlight differences in glomerular injury models, mouse backgrounds, adequacy of wash-out periods, transgene leakiness, and quantification methods, among other factors.…”

Global transcriptomic changes occur in aged mouse podocytes

“…Immunofluorescent 38,[87][88][89] and immunoperoxidase 8,11,90 staining were performed as previously described.…”

Cellular plasticity: A mechanism for homeostasis in the kidney

“…Replacement of damaged podocytes therefore relies on local kidney progenitors, of which RPCs and PECs are candidates. Cells of renin lineage have been shown to undergo mesenchymal to epithelial (MET) transformation, with an increase in Wilm's tumour suppressor1 (Wt1) gene expression and concomitant reduction in SMC markers and expression of new epithelial markers such as E‐cadherin . Animals specifically lacking WT1 in RPCs showed reduced proliferation and migration of the RPCs and worse glomerular disease than controls.…”