Kidney Week

Abstract: SA-PO345

The Role of Gata3 in Renin Cell Identity

Session Information

• Development, Organoids, Vascularized Kidneys, Nephrons, and More
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania 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

• Neyra, Jesus, University of Virginia, Charlottesville, Virginia, United States

Jesus Neyra,

• Medrano, Silvia, University of Virginia, Charlottesville, Virginia, United States

Silvia Medrano,

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

Maria Luisa S. Sequeira Lopez,

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

Roberto Ariel Gomez,

Background

Renin cells are precursors for other cell types in the kidney and show high plasticity in postnatal life in response to challenges to homeostasis. Our scRNA-seq studies revealed that the dual-zinc finger transcription factor Gata3, important for cell lineage commitment and differentiation in many tissues, is expressed in mouse renin cells under normal conditions and homeostatic threats. Based on our Chip-seq data, we found an enhancer associated with Gata3 in renin cells. In addition, we identified a potential Gata3 binding site upstream of the renin gene leading us to hypothesize that Gata3 is essential for renin cell identity.

Methods

We studied 60 and 120-day-old mice carrying a conditional deletion of Gata3 in renin cells: Gata3^fl/fl;Ren1^dCre/+ (Gata3-cKO), and control Gata3^fl/fl;Ren1^d+/+ counterparts. BUN and plasma renin levels were measured from blood samples collected by cardiac puncture. Ren1, Acta2, and Gata3 were visualized in kidney sections by immunohistochemistry. Histological analysis was performed on adult kidney sections with hematoxylin and eosin (H&E), periodic acid-Schiff (PAS) solution, or Masson’s Trichrome chemical reactions. The juxtaglomerular area (JGA) index was calculated as a ratio of renin-positive JGAs per the total number of glomeruli and expressed as a percentage.

Results

Gata3-cKO mice have: 1) a marked reduction in Gata3 staining, demonstrating Gata3 deletion in renin lineage cells; 2) a marked reduction of Ren1 and Akr1b7 mRNA levels in renin cells compared to controls; 3) a significant decrease in circulating plasma renin compared to controls under basal conditions and physiological threat; 4) a significantly reduced JGA index; 5) flattened JG cells compared to the plump and rounded morphology of control mice; 6) glomeruli with abnormal misplaced renin staining in the Bowman’s capsule; 7) an absence of cubical epithelial cells in the Bowman’s capsule, dilation of distal tubules, dilation of the glomerular capillaries and evidence of glomerular sclerosis and fibrosis. There was prominent glomerular hemorrhage with aneurysms and evidence of perivascular, peritubular, and periglomerular infiltration of inflammatory cells; 8) misplaced Acta2 staining in the intraglomerular mesangium, interstitium, and Bowman’s capsule.

Conclusion

Our results suggest a role of Gata3 in the identity of the cells of the renin lineage.

Funding

• NIDDK Support