Elsevier

Kidney International

Volume 81, Issue 8, 2 April 2012, Pages 769-778
Kidney International

Original Article
Urinary secretion and extracellular aggregation of mutant uromodulin isoforms

https://doi.org/10.1038/ki.2011.456Get rights and content
Under an Elsevier user license
open archive

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.

KEYWORDS

aggregation
Tamm–Horsfall protein
urinary protein secretion
uromodulin

Cited by (0)

All the authors declared no competing interests.

9

Current address: Institute of Physiology, University of Zurich, Zurich, Switzerland.

10

Current address: Centro de Biologia Molecular Severo Ochoa, Madrid, Spain.