Abstract: TH-OR114

Biopsy Transcriptome Expression Identifies Loss of FRMD3 as a Mediator of Declining Renal Function in CKD

Session Information

  • Scarred for Life?
    November 02, 2017 | Location: Room 394, Morial Convention Center
    Abstract Time: 05:42 PM - 05:54 PM

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Brennan, Eoin P., University College Dublin, Dublin, Ireland
  • McEvoy, Caitriona M., University College Dublin, Dublin, Ireland
  • Gough, Oisín, University College Dublin, Dublin, Ireland
  • McAnallen, Susan Marie, University College Dublin, Dublin, Ireland
  • Rodzlan Akib, Mohd Radzi, Beaumont Hospital, Dublin, Ireland
  • Dorman, Anthony M., Beaumont Hospital, Dublin, Ireland
  • Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
  • Sadlier, Denise M, University College Dublin, Dublin, Ireland
  • Godson, Catherine, University College Dublin, Dublin, Ireland

Group or Team Name

  • GENIE Consortium
Background

We have generated global transcriptome profiles of renal biopsies from patients with chronic kidney disease (CKD). Here, we investigated the relationship between renal gene expression and clinical parameters of kidney function, and identify an association between loss of Ferm domain-containing protein 3 (FRMD3) and a decline in renal function.

Methods


We performed RNA-Seq gene expression profiling on material obtained from patients undergoing clinically indicated biopsy (n=44). Using this phenotypically heterogenous cohort of patients, the association of gene expression with clinical parameters [tubulointerstitial fibrosis (TIF) score, eGFR, serum creatinine, glomerular basement membrane thickness] was investigated. Follow-up clinical data (serum creatinine measurements 3-6 years post-biopsy) was used to identify gene expression profiles predictive of disease progression. Subsets of genes were identified that were significantly associated (FDR P<0.05) with these parameters of kidney disease.

Results

Pathway analyses identified enrichment for pro-inflammatory signalling (e.g. T-cell infiltration, TNF-α, NF-κB, IFN-γ, CD3) in patients with severe CKD. 1,590 genes were significantly associated with renal decline in these patients during a 3-6 year follow-up period (FDR P<0.05), including loss of FRMD3 expression (FDR P=0.006). Interestingly, large scale genome-wide association studies have recently implicated FRMD3 as a genetic candidate in kidney disease. Using functional studies we investigated the role of FRMD3 in renal cells using in vitro models of renal fibrosis. Here, FRMD3 knockdown caused exaggerated fibrotic responses to TGF-β1 in renal tubule epithelial cells. Finally, mass spectrometry analysis of FRMD3 binding partners indicated interactions with mitochondrial respiratory chain components (complex I, III and V).

Conclusion

Taken together, these data implicate FRMD3 as a novel regulator of renal function in CKD.

Funding

  • NIDDK Support