A Novel Role for FERM Domain-Containing Protein 3 in CKD

Key Points We have identified a transcriptional signature of 93 genes associated with CKD severity and progression. Protein 4.1, ezrin, radixin, moesin domain-containing protein 3 gene expression is reduced in the context of more severe kidney disease and in individuals who go on to develop progressive disease. Protein 4.1, ezrin, radixin, moesin domain-containing protein 3 interacts with proteins of the cell cytoskeleton and cell-cell junctions in proximal tubule epithelial cells. Background Currently, there are limited methods to link disease severity and risk of disease progression in CKD. To better understand this potential relationship, we interrogated the renal transcriptomic profile of individuals with CKD with measures of CKD severity and identified protein 4.1, ezrin, radixin, moesin-domain containing protein 3 ( FRMD3 ) as a candidate gene for follow-up study. Methods RNA-sequencing was used to profile the transcriptome of CKD biopsies from the North Dublin Renal BioBank, the results of which were correlated with clinical parameters. The potential function of FRMD3 was explored by interrogating the FRMD3 interactome and assessing the effect of lentiviral mediated FRMD3 knock down on human renal proximal tubule epithelial cells by assessing cell viability, metabolic activity, and structural markers. Results We identified a subset of 93 genes which are significantly correlated with eGFR and percentage tubulointerstitial fibrosis at time of biopsy and with CKD progression 5 years postbiopsy. These results were validated against transcriptomic data from an external cohort of 432 nephrectomy samples. One of the top-ranking genes from this subset, FRMD3, has previously been associated with the risk of developing diabetic kidney disease. Interrogating the interactome of FRMD3 in tubule epithelial cells revealed interactions with cytoskeletal components of cell-cell junctions. Knockdown of FRMD3 expression in tubule epithelial cells resulted in increased proapoptotic activity within the cells, as well as dysregulation of E-Cadherin. Conclusions We have identified a panel of kidney-specific transcripts correlated with severity and progression of kidney disease, and from this, we have identified a possible role for FRMD3 in tubule cell structure and health.

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Publication Details

Journal
Kidney360
Published
2024-10-16
DOI
https://doi.org/10.34067/kid.0000000602
Citations
3
Primary Topic
Renal and related cancers
Type
article
Field-Weighted Citation Impact
0.70

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article

A Novel Role for FERM Domain-Containing Protein 3 in CKD

Joel N. Hirschhorn, Viji Nair, Bianca Crifò, Per‐Henrik Groop et al.
3 citations
Kidney360
Renal and related cancers
0.70
article

A Novel Role for FERM Domain-Containing Protein 3 in CKD

Joel N. Hirschhorn, Viji Nair, Bianca Crifò, Per‐Henrik Groop, Maria Hughes, Eoin Brennan, Daniel Crean, Eugène Dillon, Xin Sheng, José C. Florez, Andrew Gaffney, Niina Sandholm, Gareth J. McKay, Finian Martin, Katalin Suszták, Oisin Gough, Zhengzi Yi, Darrell Andrews, Javier Rodríguez, Amy Jayne McKnight, Ross Doyle, Matthias Kretzler, Peter J. Conlon, Ciarán Kennedy, Caitríona M. McEvoy, Alexander P. Maxwell, Catherine Godson, David Matallanas, Weijia Zhang, Susan Kennedy, Denise M. Sadlier, Anthony Dorman, Susan MC Anallen
article en
3 citations

Abstract

Key Points We have identified a transcriptional signature of 93 genes associated with CKD severity and progression. Protein 4.1, ezrin, radixin, moesin domain-containing protein 3 gene expression is reduced in the context of more severe kidney disease and in individuals who go on to develop progressive disease. Protein 4.1, ezrin, radixin, moesin domain-containing protein 3 interacts with proteins of the cell cytoskeleton and cell-cell junctions in proximal tubule epithelial cells. Background Currently, there are limited methods to link disease severity and risk of disease progression in CKD. To better understand this potential relationship, we interrogated the renal transcriptomic profile of individuals with CKD with measures of CKD severity and identified protein 4.1, ezrin, radixin, moesin-domain containing protein 3 ( FRMD3 ) as a candidate gene for follow-up study. Methods RNA-sequencing was used to profile the transcriptome of CKD biopsies from the North Dublin Renal BioBank, the results of which were correlated with clinical parameters. The potential function of FRMD3 was explored by interrogating the FRMD3 interactome and assessing the effect of lentiviral mediated FRMD3 knock down on human renal proximal tubule epithelial cells by assessing cell viability, metabolic activity, and structural markers. Results We identified a subset of 93 genes which are significantly correlated with eGFR and percentage tubulointerstitial fibrosis at time of biopsy and with CKD progression 5 years postbiopsy. These results were validated against transcriptomic data from an external cohort of 432 nephrectomy samples. One of the top-ranking genes from this subset, FRMD3, has previously been associated with the risk of developing diabetic kidney disease. Interrogating the interactome of FRMD3 in tubule epithelial cells revealed interactions with cytoskeletal components of cell-cell junctions. Knockdown of FRMD3 expression in tubule epithelial cells resulted in increased proapoptotic activity within the cells, as well as dysregulation of E-Cadherin. Conclusions We have identified a panel of kidney-specific transcripts correlated with severity and progression of kidney disease, and from this, we have identified a possible role for FRMD3 in tubule cell structure and health.

Kidney360Vol. 5(12)
University College Dublin (IE), Broad Institute (US), University of Helsinki (FI), Royal College of Surgeons in Ireland (IE), Trinity College Dublin (IE), University of Michigan (US), Helsinki University Hospital (FI), Beaumont Hospital (IE), Mater Misericordiae University Hospital (IE), Massachusetts General Hospital (US), Queens University (BD), Children's Hospital of Zhejiang University (CN), Folkhälsans Forskningscentrum (FI), Monash University (AU), Zhejiang University (CN), University of Pennsylvania (US), Icahn School of Medicine at Mount Sinai (US)
Northwestern University, Royal College of Surgeons in Ireland, University of Bristol, Medical Research Council
Good health and well-being
Openalex Percentile: Top 29%
Renal and related cancers
0.70
DOIOpen Access PDFOpenAlex
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