Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein.

Urinary secretion and extracellular aggregation of mutant uromodulin isoforms.

GIACHINO, Daniela Francesca;DE MARCHI, Mario;AMOROSO, Antonio;
2012-01-01

Abstract

Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein.
81
8
769
778
http://www.nature.com/ki/journal/vaop/ncurrent/pdf/ki2011456a.pdf
Uromodulin; urinary excretion
Schaeffer C; Cattaneo A; Trudu M; Santambrogio S; Bernascone I; Giachino D; Caridi G; Campo A; Murtas C; Benoni S; Izzi C; De Marchi M; Amoroso A; Ghiggeri GM; Scolari F; Bachi A; Rampoldi L
File in questo prodotto:
File Dimensione Formato  
2013_Schaeffer_post-print[1].pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 265.29 kB
Formato Adobe PDF
265.29 kB Adobe PDF Visualizza/Apri
Schaeffer et al 2012 UMOD.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 620.09 kB
Formato Adobe PDF
620.09 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/98421
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 18
social impact