Establishment of cell models of Dent’s disease for the discovery of molecular targets and therapeutic solutions.

2019 edition

Mónica Durán

Dent’s Disease (DD) is a rare X-linked condition affecting proximal renal tubules caused by mutations in the CLCN5 gene that encodes for the CLC-5 exchange transporter. Clinically, it is characterized by low molecular weight proteinuria, which is a hallmark of the renal Fanconi’s syndrome, hipercalciuria, nephrocalcinosis and progression to end-stage-renal-failure. Currently, there are no treatments or ongoing clinical trials for this disease. The main function of proximal tubule cells (PTC) of the kidney is reabsorption, which relies on efficient endocytic recycling of the multiligand tandem receptor megalin-cubilin, and CLC-5 controls the acidification and recycling activity of endosomal compartments. Currently, not much is known about the mechanisms involved in DD progression, likely due to the lack of appropriate experimental models to study this disease. To study the impact caused by the lack of CLCN5 expression or by representative gene CLCN5 mutations (Class I, II or III) we have produced PTC models that, upon phenotypical characterization, have been studied by microarrays assays.  The discovery of new genes and pathways associated to different classes of CLCN5 mutations might be useful to understand DD pathophysiology and serve as biomarkers and therapeutic targets for this and, possibly, for other renal Fanconi’s syndrome related disorders. Moreover, these might lead to a better understanding of the fundamental processes affecting epithelial cell differentiation, regulation of transport mechanisms and role of tubular cells in renal disease progression.