Molecular genetics of renal disorders
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 of Henle’s loop and, to a lower extent, of the distal convoluted tubule. 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.
The main research interest of the group is to gain insight into the biology of uromodulin, its role in renal function and in chronic diseases of the kidney. The unit identified hepsin as the membrane serine protease that is responsible for uromodulin urinary release, and contributed to studies that clarified the structural bases of uromodulin polymerization.
The UMOD gene represents a paradigm of continuous genetic risk of disease, from rare mutations causing Mendelian disease to common alleles associated with complex traits.
Mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), leading to renal damage and chronic kidney disease (CKD). The group showed that uromodulin mutations lead to ER retention of mutant protein, ER stress and Unfolded Protein Response (UPR) activation, and early induction of inflammation. The group recently demonstrated that a similar mechanism, i.e. ER retention and UPR activation, is observed for mutations in renin that are localized in the mature protein, and lead to a related form of ADTKD.
Common 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 such 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.
By studying molecular mechanisms our research has the final goal to identify novel therapeutic targets for renal disease and hypertension.
Schaeffer C, Devuyst O, Rampoldi L. (2021) Uromodulin: Roles in Health and Disease. Annu Rev Physiol. 83:477-501. doi: 10.1146/annurev-physiol-031620-092817.
Kidd K, Vylet’al P, Schaeffer C, Olinger E, Živná M, Hodaňová K, Robins V, Johnson E, Taylor A, Martin L, Izzi C, Jorge SC, Calado J, Torres RJ, Lhotta K, Steubl D, Gale DP, Gast C, Gombos E, Ainsworth H, Chen YM, Almeida JR, Fernandes de Souza C, Silveira C, Raposeiro R, Weller N, Conlon P, Murray S, Benson KA, Cavalleri G, Votruba M, Vrbacká A, Amoroso A, Gianchino D, Caridi G, Ghiggeri GM, Divers J, Scolari F, Devuyst O, Rampoldi L*, Kmoch S, Bleyer A* (2020) Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations. Kidney Int. Rep. 5(9):1472-1485. doi: 10.1016/j.ekir.2020.06.029.
Stsiapanava A, Xu C, Brunati M, Schaeffer C, Zamora-Caballero S, Algarra B, Han L, Carroni M, Yasumasu S, Rampoldi L, Wu B, Jovine L (2020) Cryo-EM Structure of Native Human Uromodulin, a Zona Pellucida Module Polymer. EMBO J. 39(24):e106807. doi: 10.15252/embj.2020106807.
Schaeffer C, Izzi C, Vettori A, Pasqualetto E, Cittaro D, Lazarevic D, Caridi G, Gnutti B, Mazza C, Jovine L, Scolari F, Rampoldi L (2019) Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein. Sci Rep. 9(1):11601. doi: 10.1038/s41598-019-48014-6.
Devuyst O, Olinger E, Weber S, Eckardt KU, Kmoch S, Rampoldi L, Bleyer AJ. (2019) Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers. 5(1):60.
Trudu M, Schaeffer C, Riba M, Ikehata M, Brambilla P, Messa P, Martinelli-Boneschi F, Rastaldi MP, Rampoldi L (2017) Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations. Sci Rep. 7(1):7383. doi: 10.1038/s41598-017-07804-6.
Schaeffer C, Merella S, Pasqualetto E, Lazarevic D, Rampoldi L (2017) Mutant uromodulin expression leads to altered homeostasis of the endoplasmic reticulum and activates the unfolded protein response. PLoS One. 12(4):e0175970. doi: 10.1371/journal.pone.0175970.
Ghirotto S, Tassi F, Barbujani G, Pattini L, Hayward C, Vollenweider P, Bochud M, Rampoldi L*, Devuyst O* (2016) The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution. J Am Soc Nephrol. 27(10):2983-2996. doi: 10.1681/ASN.2015070830.
Brunati M, Perucca S, Han L, Cattaneo A, Consolato F, Andolfo A, Schaeffer C, Olinger E, Peng J, Santambrogio S, Perrier R, Li S, Bokhove M, Bachi A, Hummler E, Devuyst O, Wu Q, Jovine L, Rampoldi L (2015) The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin. Elife. 4:e08887. doi: 10.7554/eLife.08887.
Trudu M, Janas S, Lanzani C, Debaix H, Schaeffer C, Ikehata M, Citterio L, Demaretz S, Trevisani F, Ristagno G, Glaudemans B, Laghmani K, Dell’Antonio G, the SKIPOGH team, Loffing J, Rastaldi MP, Manunta P, Devuyst O, Rampoldi L (2013) Common noncoding UMOD variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med. 19(12):1655-60. doi: 10.1038/nm.3384.