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Abstract: TH-PO187

Investigating the Role of Early B Cell Factor 1 (EBF1) in Maintaining the Integrity of the Glomerular Filtration Barrier

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Andrews, Darrell C., University College Dublin, Dublin, Ireland
  • Davis, Jessica L., University College Dublin, Dublin, Ireland
  • Brennan, Eoin, University College Dublin, Dublin, Ireland
  • Crean, John, University College Dublin, Dublin, Ireland
  • Godson, Catherine, University College Dublin, Dublin, Ireland
Background

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) and organ failure worldwide. Current therapies are inadequate. Proteinuria is a hallmark of DKD and the onset of progressive proteinuria is associated with disease progression and reflects loss of glomerular filtration barrier (GFB) integrity. Defining the underlying mechanisms that lead to a compromised GFB during the progression of DKD is key to developing effective therapeutic strategies. EBF1 was previously identified by our GWAS analysis in a case (individuals with T1DM) vs. control (individuals with T1DM and no evidence of renal disease 15 years post-diagnosis) approach as associated with macroalbuminuria and ESRD (DOI: 10.1681/ASN.2019030218), however the precise mechanisms underlying the function of this gene in the kidney remain elusive.

Methods

In order to investigate the functional role of EBF1 in the kidney we utilised primary human mesangial cells and iPSC derived organoid cultures.

Results

Our previous investigations in Tg(l-fabp:DBP:EGFP) zebrafish demonstrated that morpholino mediated knockdown of EBF1 resulted in the loss of an albumin-like florescent tracer protein from the circulation and the development of generalised edema in zebrafish larvae, suggesting compromised glomerular barrier integrity in the absence of EBF1 and supporting a role for this gene in kidney function. EBF1 expression was investigated during iPSC derived organoid development. EBF1 was found to be most highly expressed in stromal cell populations. To investigate the precise molecular mechanisms underlying the functional role of EBF1 in such populations bulk RNA sequencing analysis was used to map deregulated transcripts in EBF1 knockdown human primary mesangial cells vs control. EBF1 target genes were inferred using motif enrichment analysis.

Conclusion

These findings further support a role for EBF1 in maintaining the integrity of the glomerular barrier integrity.

Funding

  • Government Support – Non-U.S.