Kidney Week

Abstract: FR-PO937

ZEB2 in Renal Stromal Progenitors Regulates Nephrogenesis and Nephron Endowment in Mice

Session Information

• Development, Stem Cells, Regenerative Medicine - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

• Kumar, Sudhir, Boston University Medical Center, Boston, Massachusetts, United States

Sudhir Kumar,

• Lu, Weining, Boston University Medical Center, Boston, Massachusetts, United States

Weining Lu,

Background

ZEB2 is a SMAD-interacting transcription factor that is mutated in Mowat-Wilson syndrome, a congenital disorder with renal anomalies. ZEB2 is highly expressed in developing kidney stromal progenitors and is a target gene for FOXD1, a transcription factor and an early marker for renal stromal progenitors. FOXD1 regulates nephrogenesis and nephron endowment during kidney development while Foxd1 knockout mice have aberrant ZEB2 expression. However, the role of ZEB2 in nephrogenesis and nephron endowment is not known.

Methods

We analyzed the nephrogenesis and nephron endowment in Zeb2 stroma-specific conditional knockout mice Zeb2^flox/flox;Foxd1Cre⁺ (Zeb2 cKO) and their wild-type littermate controls. Glomerular numbers were quantified by direct counting using kidney histology and nephrin immunostaining. Nephron progenitors were analyzed using SIX2, WT1 and PAX2 markers. Nephrogenesis was analyzed by immunostaining using nephron morphogenesis markers Jagged1, megalin, uromodulin, pan-cytokeratin and Dolichos Biflorus Agglutinin (DBA). Cell proliferation in developing kidney was analyzed by phospho-Histone H3.

Results

We found that Zeb2 cKO had significantly less glomerular numbers at newborn and 3 weeks old compared to wild type littermate controls (p<0.01). Immunohistochemical analysis showed that newborn Zeb2 cKO kidneys have fewer SIX2+ nephron progenitors compared to wild type littermate controls. This result was also confirmed by WT1 and PAX2 immunostaining. Jagged1, megalin, and uromodulin staining demonstrated abnormal nephron structure in Zeb2 cKO kidneys. Pan-cytokeratin and DBA staining showed defective ureteric branching morphogenesis. Newborn Zeb2 cKO mice also have reduced cell proliferation in the nephrogenic zone as compared to wild type littermate controls.

Conclusion

ZEB2 in renal stromal progenitors regulates SIX2+ nephron progenitor self-renewal and differentiation. Loss of Zeb2 in renal stromal progenitors leads to abnormal nephrogenesis, low nephron endowment and congenital renal anomalies.

Funding

• NIDDK Support