Urinary renal epithelial cells can be used for <i>NPHP1</i> phenotyping and a personalized therapeutic strategy

Sudhindar, Praveen;Olinger, Eric;Sentell, Zachary;Mabillard, Holly;Arcila-Galvis, Juliana;et.al.
(2025) Journal of Cell Science — Vol. 138, n° 20 (2025)

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  • Sudhindar, PraveenTranslational and Clinical Research Institute 1 , Faculty of Medical Sciences , , Central Parkway, Newcastle upon Tyne, NE1 3BZ ,
    Author
  • Olinger, Ericorcid-logoTranslational and Clinical Research Institute 1 , Faculty of Medical Sciences , , Central Parkway, Newcastle upon Tyne, NE1 3BZ and 2Center for Human Genetics, Cliniques Universitaires Saint-Luc, Brussels, Belgium
    Author
  • Sentell, Zacharyorcid-logoBiosciences Institute 3 , Faculty of Medical Sciences , , Central Parkway, Newcastle upon Tyne, NE1 3BZ ,
    Author
  • Mabillard, Hollyorcid-logoTranslational and Clinical Research Institute 1 , Faculty of Medical Sciences , , Central Parkway, Newcastle upon Tyne, NE1 3BZ ,
    Author
  • Arcila-Galvis, Julianaorcid-logoBiosciences Institute 3 , Faculty of Medical Sciences , , Central Parkway, Newcastle upon Tyne, NE1 3BZ ,
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Abstract
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.
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Sudhindar, P., Olinger, E., Sentell, Z., Mabillard, H., Dicka, B., Wood, K., Rutland, D., Collins, C., Trevisan-Herraz, M., Sayer, J., & Arcila-Galvis, J. (2025). Urinary renal epithelial cells can be used for <i>NPHP1</i> phenotyping and a personalized therapeutic strategy. Journal of Cell Science, 138(20). https://doi.org/10.1242/jcs.264141 (Original work published 2025)