Urinary secretion and extracellular aggregation of mutant uromodulin isoforms

Céline Schaeffer, Angela Cattaneo, Matteo Trudu, Sara Santambrogio, Ilenia Bernascone, Daniela Giachino, Gianluca Caridi, Andrea Campo, Corrado Murtas, Simona Benoni, Claudia Izzi, Mario De Marchi, Antonio Amoroso, Gian Marco Ghiggeri, Francesco Scolari, Angela Bachi, Luca Rampoldi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)769-778
Number of pages10
JournalKidney International
Volume81
Issue number8
DOIs
Publication statusPublished - Apr 2 2012

Keywords

  • aggregation
  • Tamm-Horsfall protein
  • urinary protein secretion
  • uromodulin

ASJC Scopus subject areas

  • Nephrology

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