Type of uromodulin mutation and allelic status influence onset and severity of uromodulinassociated kidney disease in mice

Abstract

Uromodulin-associated kidney disease(UAKD) is adominant heritable renal disease inhumans which is caused by mutations in the uromodulin (UMOD) gene and characterized by heterogeneous clinical appearance. To get insights into possible causes of this heterogeneity of UAKD, we describe the new mutant mouse line UmodC93F, leading to disruption of a putative disulfide bond which is also absent in a known human UMOD mutation, and comparethe phenotype of thisnewmouseline with the recently publishedmouselineUmodA227T. Inboth mutant mouse lines, which were both bred on the C3H background, the Umod mutations cause a gain-of-toxic function due to amaturation defect of the mutant uromodulin leading to a dysfunction of thick ascending limb of Henle's loop (TALH) cells of the kidney. Umod mutant mice exhibit increased plasma urea and Cystatin levels, impaired urinary concentration ability, reduced fractional excretion of uric acid and nephropathological alterations including uromodulin retention in TALH cells, interstitial fibrosis and inflammatory cell infiltrations, tubular atrophy and occasional glomerulo- und tubulocystic changes, a phenotype highly similar to UAKD in humans. The maturation defect of mutant uromodulin leads to the accumulation of immature uromodulin in the endoplasmic reticulum (ER) and toERhyperplasia. Further, this studywasable to demonstrate for the first time in vivo that the severity of the uromodulin maturation defect as well as onset and speed of progression of renal dysfunction and morphological alterationsare strongly dependentonthe particularUmodmutation itselfandthe zygosity status. © The Author 2013. Published by Oxford University Press. All rights reserved.