Dent's disease is a rare genetic kidney disorder that affects the proper functioning of the kidneys and is caused by mutations in the CLCN5 gene. This gene encodes the ClC-5 protein, which regulates the acidification of endosomes, compartments of the cell involved in protein transport. The disease is characterised by the loss of low molecular weight proteins in the urine. It also leads to chronic kidney disease and renal fibrosis, and ultimately to kidney failure. The project has been made possible thanks to the support of the Dent Disease Association (ASDENT)

But how do we go from a mutation in a gene to renal fibrosis? To better understand the pathophysiological processes, the Renal Pathophysiology Research Group at the Vall d'Hebron Research Institute (VHIR) generated cellular models of the disease. These models reproduced most of the characteristics and made it possible to study the molecular mechanisms that lead from a mutation in the CLCN5 gene to the dysfunction of the renal proximal tubule (the part of the kidney responsible for reabsorbing proteins to prevent their loss through the urine).

In a recent study published in the journal Life Science Alliance, researchers from the same group used these cellular models, as well as animal models* of the disease, to understand the molecular and cellular mechanisms linking the loss of ClC-5 function to the progression to renal fibrosis. The results of this research showed that the CLC-5 protein regulates collagen levels I and IV (components of fibrotic renal tissue) through the β-catenin pathway and lysosomal degradation. When ClC-5 is not functional, the β-catenin pathway is activated, leading to increased collagen synthesis. Under normal circumstances, lysosomes are responsible for degrading excess or poor-quality collagen. However, when ClC-5 is mutated (as in Dent's disease), lysosomal acidification (organelles responsible for eliminating proteins that the cell does not need) is altered, resulting in impaired collagen degradation. So, if we have a lot more collagen on the one hand, and a lot less degradation on the other, accumulation occurs, leading to fibrosis development.

"The results of this research will help understand and develop therapeutic strategies not only for Dent's disease but also for other kidney diseases that progress to fibrosis. Currently, there are no specific drugs to prevent the progression of this particular disease, and diagnosis is difficult due to the large phenotypic variability among patients. As a result, the only therapeutic options for patients so far are dialysis or transplantation," explains Dr. Gerard Cantero-Recasens, principal investigator of the Renal Pathophysiology Group.

Furthermore, as Dr. Anna Meseguer, head of the Renal Pathophysiology Group at VHIR, explains, "the study of paediatric genetic diseases allows us to more easily identify mechanisms related to the loss of renal function. This is because they are caused by unique mutations and there are no associated pathologies which could mask or hinder the study of cellular and molecular processes. In fact, thanks to this type of research, we can learn more about the disease and gain more knowledge about human biology and renal pathophysiology." The study was carried out in collaboration with Dr. Gema Ariceta, Head of the Paediatric Nephrology Service at Vall d'Hebron Hospital, and Dr. Baisong Lu from the Wake Forest Institute (USA).

It is worth noting that the work has had the support of the Dent Disease Association (ASDENT), a non-profit association created in 2011 with the aim of raising funds for Dent's disease research. It has consistently supported the development of this project over the last 10 years. This work has also been possible thanks to the financial support of the Carlos III Health Institute, the Mizutani Foundation for Glycoscience, the SENEFRO Foundation, and the Ministry of Science and Innovation.

* Institutional statement on the use of animal experiments