Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function

Durán, Mónica; Burballa Tàrrega, Carla, 1988-; Cantero Recasens, Gerard, 1984-; Butnaru, Cristian M.; Malhotra, Vivek; Ariceta, Gema; Sarró, Eduard; Meseguer Navarro, Anna

doi:http://dx.doi.org/10.1093/hmg/ddab131

Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function

Llicència

Citació

Durán M, Burballa C, Cantero-Recasens G, Butnaru CM, Malhotra V, Ariceta G et al. Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function. Hum Mol Genet. 2021 Jul 9;30(15):1413-28. DOI: 10.1093/hmg/ddab131

Resum

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.