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Published on: July 29, 2016
Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function
Mónica Durán1, Carla Burballa1,2, Gerard Cantero-Recasens1
1Renal Physiopathology Group, Vall d'Hebron Research Institute (VHIR)-CIBBIM Nanomedicine, Barcelona, Spain.
Abstract:
Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria and variable degree of hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressing to chronic kidney disease. Although mutations in the electrogenic Cl-/H+ antiporter ClC-5, which impair endocytic uptake in proximal tubule cells, cause the disease, there is poor genotype-phenotype correlation and their contribution to proximal tubule dysfunction remains unclear. To further discover the mechanisms linking ClC-5 loss-of-function to proximal tubule dysfunction, we have generated novel DD1 cellular models depleted of ClC-5 and carrying ClC-5 mutants p.(Val523del), p.(Glu527Asp) and p.(Ile524Lys) using the human proximal tubule-derived RPTEC/TERT1 cell line. Our DD1 cellular models exhibit impaired albumin endocytosis, increased substrate adhesion and decreased collective migration, correlating with a less differentiated epithelial phenotype. Despite sharing functional features, these DD1 cell models exhibit different gene expression profiles, being p.(Val523del) ClC-5 the mutation showing the largest differences. Gene set enrichment analysis pointed to kidney development, anion homeostasis, organic acid transport, extracellular matrix organization and cell-migration biological processes as the most likely involved in DD1 pathophysiology. In conclusion, our results revealed the pathways linking ClC-5 mutations with tubular dysfunction and, importantly, provide new cellular models to further study DD1 pathophysiology.
Insights
Dent disease 1 (DD1) cellular models reveal mechanisms linking ClC-5 mutations to kidney tubule dysfunction. These models show impaired cell functions and identify key biological pathways involved in DD1.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Dent disease 1 (DD1) is an X-linked renal proximal tubulopathy caused by mutations in the ClC-5 gene.
- ClC-5 dysfunction impairs endocytic uptake in proximal tubule cells, but the precise mechanisms of tubular dysfunction remain unclear.
- Existing knowledge lacks a clear genotype-phenotype correlation for DD1.
Purpose of the Study:
- To generate and characterize novel cellular models of DD1.
- To investigate the functional consequences of ClC-5 loss-of-function and specific mutations in proximal tubule cells.
- To identify molecular pathways involved in DD1 pathophysiology.
Main Methods:
- Generation of DD1 cellular models using RPTEC/TERT1 cells with ClC-5 depletion and specific mutants (p.Val523del, p.Glu527Asp, p.Ile524Lys).
- Assessment of cellular functions including albumin endocytosis, substrate adhesion, and collective migration.
- Analysis of gene expression profiles and utilization of gene set enrichment analysis.
Main Results:
- DD1 cellular models demonstrated impaired albumin endocytosis, increased substrate adhesion, and reduced collective migration.
- These functional deficits correlated with a less differentiated epithelial phenotype.
- Gene set enrichment analysis implicated kidney development, anion homeostasis, organic acid transport, extracellular matrix organization, and cell migration in DD1.
Conclusions:
- The study identified specific pathways linking ClC-5 mutations to proximal tubule dysfunction in DD1.
- Novel DD1 cellular models were developed, providing valuable tools for further research into the disease.
- These models facilitate a deeper understanding of DD1 pathophysiology and potential therapeutic targets.
