Kidney Week

Abstract: TH-PO0539

Transcription Factor ZEB2 Regulates Differentiation of FOXD1+ Stromal Progenitors into Cells of Renin Lineage in the Kidneys

Session Information

• Development, Stem Cells, and Regenerative Medicine
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Authors

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

Sudhir Kumar, PhD

• Lu, Simon L., Boston University, Boston, Massachusetts, United States

Simon L. Lu

• Yan, Kun, Boston University, Boston, Massachusetts, United States

Kun Yan

• Vurkac, Omer Ege, Boston University, Boston, Massachusetts, United States

Omer Ege Vurkac

• Fu, Jiayi, Boston University, Boston, Massachusetts, United States

Jiayi Fu

• Fan, Xueping, Boston University, Boston, Massachusetts, United States

Xueping Fan, PhD

• Zhang, Jie, Boston University, Boston, Massachusetts, United States

Jie Zhang, PhD

• Wei, Jin, Boston University, Boston, Massachusetts, United States

Jin Wei, PhD

• Sequeira Lopez, Maria Luisa S., University of Virginia School of Medicine, Charlottesville, Virginia, United States

Maria Luisa S. Sequeira Lopez, MD

• Gomez, Roberto Ariel, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Roberto Ariel Gomez, MD

• Salant, David J., Boston University, Boston, Massachusetts, United States

David J. Salant, MD, MBChB

• Zhang, Chao, Boston University, Boston, Massachusetts, United States

Chao Zhang, PhD

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

Weining Lu, MD, MS, FASN

Background

Cells of renin lineage (CoRL), located in the juxtaglomerular apparatus of the kidney, play a critical role in maintaining arterial blood pressure and fluid-electrolyte balance. In addition to their endocrine function, CoRL also serve as multipotent progenitors capable of transdifferentiating into podocytes and parietal epithelial cells (PECs) in both human and murine models of glomerular disease. During kidney development, CoRL originate from FOXD1-positive stromal progenitors. However, the molecular mechanisms regulating the differentiation of FOXD1-positive progenitors into CoRL remain poorly understood. Zinc finger E-box-binding homeobox 2 (ZEB2), a transcription factor highly expressed in FOXD1-positive kidney stromal progenitors, has been shown to regulate their differentiation. Therefore, we tested if ZEB2 is required for the differentiation of FOXD1-positive kidney stromal progenitors into CoRL.

Methods

We analyzed the Zeb2^flox/flox;Foxd1Cre⁺ conditional knockout mice (Zeb2 cKO) and their wild-type (WT) littermate controls. Single-cell RNA sequencing (scRNA-seq) was performed on kidney tissues from 3-week-old Zeb2 cKO and WT mice using the 10x Genomics Chromium platform. The data were analyzed using our in-house computational pipeline. Immunostaining was performed to validate scRNA-seq findings.

Results

Zeb2 cKO mice exhibited a reduced number of renin-expressing cells and lower arterial blood pressure compared to WT controls. The scRNA-seq and gene expression analysis revealed ectopic expression of podocyte and PEC markers (WT1, TLE4, and CLDN1) within the vascular compartment of Zeb2 cKO kidneys. Trajectory and functional enrichment analyses identified significant alterations in angiogenesis and chromatin remodeling pathways in Zeb2 cKO kidneys.

Conclusion

ZEB2 is a key regulator of FOXD1-positive stromal progenitor cell fate. In the absence of ZEB2, FOXD1-positive stromal progenitors adopt a podocyte- and PEC-like cell fate rather than CoRL, indicating that ZEB2 is a critical determinant of stromal progenitor lineage commitment for CoRL during kidney development.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025nk55ss2h