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Lookup NU author(s): Dr Eric OlingerORCiD, Zac Sentell, Dr Holly MabillardORCiD, Dr Katrina Wood, Dr Dom Rutland, Dr Marco Trevisan Herraz, Professor John SayerORCiD, Dr Juliana Arcila GalvisORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025. Published by The Company of Biologists. Nephronophthisis (NPHP) is a recessive tubulointerstitial nephropathy and a leading genetic cause of kidney failure in children and young adults. The most common genetic cause is a homozygous deletion of NPHP1, which encodes nephrocystin-1, a protein essential for primary cilium structure and cell junctions. Using personalized medicine and deep phenotyping, we investigated a family with three siblings carrying a homozygous NPHP1 deletion. We compared kidney biopsy tissue and human urine-derived renal epithelial cells (hURECs) from these individuals. Bulk RNA-seq on patient hURECs revealed altered expression in EGFR signalling, extracellular components and adherens junctions, which is consistent with the known roles for nephrocystin-1. Treatment with alprostadil, a proposed NPHP therapy, increased ciliation but worsened ciliary elongation. By contrast, the EGFR kinase inhibitor AG556 rescued of ciliary length and morphology. Transcriptional profiling post-treatment showed AG556 reversed the disease signature more effectively that alprostadil. These findings suggest that EGFR inhibition might offer a more promising therapeutic strategy for NPHP1-associated renal ciliopathy, warranting further testing in in vivo models before clinical application.
Author(s): Sudhindar PD, Olinger E, Sentell ZT, Mabillard H, Dicka B, Wood K, Rutland D, Collins C, Trevisan-Herraz M, Sayer JA, Arcila-Galvis JE
Publication type: Article
Publication status: Published
Journal: Journal of Cell Science
Year: 2025
Volume: 138
Issue: 20
Print publication date: 01/10/2025
Online publication date: 08/09/2025
Acceptance date: 02/08/2025
Date deposited: 30/09/2025
ISSN (print): 0021-9533
ISSN (electronic): 1477-9137
Publisher: The Company of Biologists Ltd
URL: https://doi.org/10.1242/jcs.264141
DOI: 10.1242/jcs.264141
Data Access Statement: The gene quantification data for all samples, including expression values for each gene across the genome, are publicly available and can be accessed at https://github.com/juearcilaga/hUREC_NPHP1_RNAseq.git RNA datasets have been submitted to GEO NCBI database, study accession ID GSE301183. The full results of the differential expression analysis are in Table S1 and functional enrichment analysis are in Table S3. All the data supporting the findings of this study are available within the article and its supplementary materials.
PubMed id: 40776899
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