ESR 6: Role of UMOD : from GWAS to Mendelian disorders, chronic kidney disease and hypertension

Supervisor: Olivier Devuyst

PhD Student: Marta Mariniello

Short Summary

The aim of this project will be to understand how quantitative variations in UMOD physiology predispose to CKD. UMOD, the most abundant protein in urine, is produced by the epithelial cells lining the thick ascending limb (TAL) of the loop of Henle, a tubular segment regulating blood pressure, water balance, and biomineralization. Recent insights suggest UMOD regulates salt transport and urinary concentration; protects against urinary tract infection and kidney stones; and plays a role in innate immunity. GWAS identified common UMOD variants strongly associated with the risk of CKD and hypertension and kidney stones in the general population. The level of urinary UMOD is also a biomarker reflecting the functional tubular mass. The working hypothesis is that imbalance in UMOD production may predispose to kidney damage by interaction with other renal insults that accumulate with age.

Scientific strategy


The specific objectives of ESR6 project will be to investigate: (i) the physiological regulators of UMOD production and the roles of the UMOD matrix inside the lumen of kidney tubules; (ii) the mechanisms by which UMOD mutations cause tubulointerstitial kidney disease and the role of ER/oxidative stress, unfolded protein response (UPR) and autophagy in the progression of CKD; (iii) the role of UMOD promoter variants and UMOD in complex disorders including CKD and kidney stones, and (iv) the possible benefit of pharmacological compounds interfering with UMOD production and/or processing.

Expected Results:

  1. Functional characterization of the Umod gene dosage effect over time in mouse models;
  2. Defining the role of UMOD in different models of renal disease; 
  3. Elucidating the mechanisms linking UMOD with the risk of CKD and hypertension;
  4. Validation of pathways and biomarkers studies in prospective human cohorts