Role of quality control in the early secretory compartment in Autosomal Dominant Tubulointerstitial Kidney Disease

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is a clinical entity mainly characterized by kidney damage eventually leading to loss of its function. Different genes cause this disease, including UMOD and REN, encoding for uromodulin and renin respectively. Mutations in UMOD and REN lead to intracellular accumulation of the mutant protein within the cell compartment called endoplasmic reticulum (ER), creating a condition of stress for the cell.

 In such conditions, some proteins that should reside within the ER start to be secreted. In physiological conditions proteins that escape from the ER are retrieved by specific receptors named KDEL receptors. There are 3 different receptors, called KDELR1, KDELR2 and KDELR3 whose specific role is currently not known. In ADTKD UMOD and REN models that we use in the lab, including cells and a mouse model, we observed a specific and significant increase of KDELR3. Previous studies already reported that KDELR3 expression increases when ER stress is induced, suggesting that it likely plays a specific function in such conditions. In this project we aim at investigating the role of KDELR3 in ADTKD pathogenesis. We will study the effect of modulating its level of expression to understand whether it has a positive or negative function. Also, we will employ different techniques to analyse whether under ER stress conditions KDELR3 regulates intracellular protein transport and if it activates specific signals.

 The expected results will be important to clarify the role of KDELR3 and will have relevance for ADTKD as we will gain new information on the disease mechanisms, possibly leading to new therapeutic strategies. Moreover, we will generate a fish model of ADTKD that could be used in future screening studies to identify molecules that rescue disease phenotype. Discovering the role of KDELR3 in conditions of ER stress could also be relevant for other diseases sharing a similar cellular mechanism.