Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism.
Uromodulin-associated kidney disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene. The pathogenesis of the disease is mostly unknown. In this study, we describe a novel chemically induced mutant mouse line termed Umod(A227T) exhibiting impaired renal function. The A227T amino acid exchange may impair uromodulin trafficking, leading to dysfunction of thick ascending limb cells of Henle's loop of the kidney. As a consequence, homozygous mutant mice display azotemia, impaired urine concentration ability, reduced fractional excretion of uric acid, and a selective defect in concentrating urea. Osteopenia in mutant mice is presumably a result of chronic hypercalciuria. In addition, body composition, lipid, and energy metabolism are indirectly affected in heterozygous and homozygous mutant Umod(A227T) mice, manifesting in reduced body weight, fat mass, and metabolic rate as well as reduced blood cholesterol, triglycerides, and nonesterified fatty acids. In conclusion, Umod(A227T) might act as a gain-of-toxic-function mutation. Therefore, the Umod(A227T) mouse line provides novel insights into consequences of disturbed uromodulin excretion regarding renal dysfunction as well as bone, energy, and lipid metabolism.
Kemter
Elisabeth
E
Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität Munich, Munich, Germany. kemter@lmb.uni-muenchen.de
Rathkolb
Birgit
B
Rozman
Jan
J
Hans
Wolfgang
W
Schrewe
Anja
A
Landbrecht
Christina
C
Klaften
Matthias
M
Ivandic
Boris
B
Fuchs
Helmut
H
Gailus-Durner
Valérie
V
Klingenspor
Martin
M
de Angelis
Martin Hrabé
MH
Wolf
Eckhard
E
Wanke
Ruediger
R
Aigner
Bernhard
B
D015502:Absorptiometry, Photon; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D006339:Heart Rate / Q000502:physiology; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009088:Mucoproteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D013045:Species Specificity; D014508:Urea / Q000378:metabolism* / Q000652:urine; D058949:Uromodulin
D009088:Mucoproteins; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin; D014508:Urea