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Abstract: FR-PO933

Podocyte-Specific Deletion of Early B Cell Factor 1 Minimizes Sclerotic Damage After Glomerular Injury

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Alruwaili, Shaymah Hamoud, Quinnipiac University, Hamden, Connecticut, United States
  • Nelson, Tracy, Yale university School of Medicine, New Haven, Connecticut, United States
  • Fretz, Jackie A., Yale School of Medicine, New Haven, Connecticut, United States
Background

It is now understood that podocyte loss, through sloughing and/or apoptosis, is the precipitating factor driving glomerulosclerosis. We also had previously reported that podocytes express the transcription factor Early B Cell Factor 1 (EBF1), although the function of this protein in these cells was unclear.

Methods

Utilizing a floxed version of Ebf1 and podocin-cre we eliminated EBF1 specifically from podocytes, and injured glomeruli directly with either hypertensive L-NAME injury or glomerular nephritis induced by anti-GBM serum. To identify the signaling pathways altered by EBF1 following its deletion alterations in RNA levels were compared to the chromosomal occupancy of EBF1 through ChIP-Seq.

Results

In both models of injury, EBF1 deletion from the podocytes was reno-protective. Fibrosis was reduced folowing anti-GBM serum at the at 7 and 10 days post injection. GFR decline and glomerular injury were found to be equivalent during the 20-week L-NAME hypertensive duration, however, recovery of the kidney for an additional ten-week period was dramatically accelerated when EBF1 was absent. This was reflected in the histologically as well as functionally through GFR measurement with the conditional knockout mice recovering almost half of their lost GFR within 3 weeks (no change in WT mice) and fully restoring kidney function by 10 weeks. Controls, by contrast, were not improved at the three-week mark, and only partially recovered by ten weeks. Less fibrotic injury was reflected in the RNA analysis of both models where markers of collagen formation, inflammation, and compliment and coagulation are all increased in controls. Conversely, pathway analysis performed with Metascape revealed EBF1 loss protects the integrity of the slit diaphragm components and that this is partially mediated by blunted calcium signaling, NFAT activation in the absence of EBF1. These changes were vified though clacineuin activity assay, reporter assays and western blots.

Conclusion

These results indicate that EBF1 normally promotes injury signals detrimental to the health of the podocyte through cell-intrinsic gene regulation. Deletion of this transcription factor from podocytes protects from glomerular injury at the initial stages of podocyte injury and these beneficial actions are mediated in part through minimizing NFAT signaling early in the injury process.

Funding

  • NIDDK Support