Genetics and cell biology

Molecular genetics of renal disorders

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Head of Unit

Luca Rampoldi

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Uromodulin (or Tamm-Horsfall protein) is the most abundant protein in normal urine, specifically produced in the kidney by epithelial cells of the thick ascending limb (TAL) of Henle’s loop. It plays a role in the protection against urinary tract infections (UTI) and renal stones, in salt handling in the TAL and in kidney innate immunity.

Research activity

Main research interest is to understand the biology of uromodulin, its role in renal function and in chronic diseases of the kidney. The unit recently identified the membrane serine protease hepsin as responsible for uromodulin urinary release and polymerisation.

Mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), leading to renal damage and chronic kidney disease (CKD). The unit showed that uromodulin mutations lead to ER retention of mutant protein. This primary effect leads to ER stress, activation of the Unfolded Protein Response, and early induction of inflammation that likely is a key step in ADTKD-UMOD pathogenesis. Variants in UMOD are associated with risk of CKD and hypertension.
Through human, cellular and animal studies, this research group demonstrated the biological effect of UMOD risk variants, ie increase gene expression, and their causal link with salt- sensitive hypertension and to age-dependent renal damage. The group also showed that UMOD risk alleles have been likely kept at high frequency through evolution due to their protective effect against UTI.

The UMOD gene hence represents a paradigm of continuous genetic risk of disease, from rare mutations causing Mendelian disease to common alleles associated with complex traits. By studying molecular mechanisms our research has the final goal to identify novel therapeutic targets for renal disease and hypertension.