Researchers at the Institute for Bioengineering of Catalonia (IBEC) in the Barcelona Science Park, in collaboration with scientists from Perelman School of Medicine (University of Pennsylvania) and the Gwangju Institute of Science and Technology (GIST), have identified the genes that could protect the kidney from chronic damage.

Chronic kidney disease affects more than 697 million people around the world. In total, it is estimated that 1.2 million people die each year due to this disease, which represents almost 5% of all annual deaths worldwide. Despite the enormous financial and personal burden that this entails, until now the biological mechanisms behind this condition were unknown, due to the structural and functional complexity of the kidney. 

Now, a study co-led by Dr Núria Montserrat, ICREA Research Professor and Principal Investigator of the group Pluripotency for organ regeneration at IBEC, jointly with Dr Katalin Susztak from the University of Pennsylvania, and Dr Ji-Hwan Park from the Korea Gwangju Institute of Science and Technology (GIST), reveals the genes responsible for chronic kidney disease and have shown that it is possible to reverse this deficiency, thus opening a possible therapeutic route against kidney damage. The identification was carried out using mini-kidneys created from human stem cells and generated in the laboratory using bioengineering techniques. In the study, published in the journal Cell Metabolism, they also demonstrated in animal models that it is possible to reverse this deficiency. 

Using innovative techniques such as single cell RNA-sequencing, the researchers unraveled the crucial role that lipid metabolism genes play in protecting against chronic kidney failure. For this, the analyzes were carried out with animal models and human mini-kidneys. The results were validated using almost one hundred patient samples. 

In healthy adults, each of our kidneys contains an average of 1.5 million nephrons, the basic functional units of the kidney that constantly filter waste products from the blood. Among the different cells that make up these filtration units, the epithelial cells of the proximal tubule of the nephron are responsible for reabsorbing water and solutes, representing 90% of the total renal mass. In almost all cases of chronic kidney disease, damage occurs in these cells, but until now, it was not known which cellular mechanisms were responsible for such dysfunction. 

By sequencing the RNA of each of the thousands of cells present in the kidney, the researchers observed for the first time important differences between healthy and diseased cells in the proximal tubule. Specifically, in the kidneys of mice with chronic kidney disease, they detected that a greater proportion of the proximal tubule cells had a different molecular signature than that found in the kidneys of healthy animals. 

Noting these observations, the IBEC researchers went one step further and, using human mini-kidneys, demonstrated that these changes were due to a decrease in the expression of some of the genes that regulate lipid metabolism in proximal tubule cells. Furthermore, “thanks to a multidisciplinary approach, using animal models and human mini-kidneys that we generate through bioengineering at IBEC, we discovered that, by correcting this deficiency, the proximal tubule cells could regain their function in the different study models,” explains Dr Montserrat, who is also a member of the Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER BBN). 

» Reference article: Dhillon P, Park J, Hurtado Del Pozo C, et al. “The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation”. Cell Metabolism. 2020 Dec. DOI: 10.1016/j.cmet.2020.11.011

» For futther information: IBEC website [+]