Uromodulin is a glycoprotein that is encoded by the UMOD gene in humans. Uromodulin is supposed to protect from urinary tract infections and the formation of kidney stones. It is the most abundant protein in mammalian urine and is synthesized exclusively and abundantly in the cells of the thick ascending limb of Henle’s loop (TALH). The main function of Henle’s loop is to create hyperosmotic urine in relation to the osmotic situation in the blood.
Uromodulin-storage disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene, causing intracellular accumulation of this protein resulting in three distinct syndroms. However, the pathogenesis of many symptoms associated with these diseases is mostly unknown so far.
The mutant mouse line UmodA227T which exhibits a phenotype similar to uromodulin storage disease in humans was analysed in the German Mouse Clinic. The aim was to investigate the effect of the disease on renal function and urinary excretion of solutes as well as its impact on other organ systems. The comprehensive analysis indeed revealed alterations when compared with wild-type animals. The mutant mice had abnormally high levels of nitrogen containing waste products in the blood and were not able to concentrate the urine properly. Thus they had increased amounts of daily urine volume. Both findings suggest renal dysfunction or altered metabolic processes in the kidney. Additionally, the body weight, fat mass and metabolic rate and cholesterol levels are reduced. Another interesting finding was that the renal excretion of calcium was increased compared to wild-type mice. In the long run this leads to reduced bone density (Osteopenia) in mutant mice.
The UmodA227T mouse line provides novel insights into consequences of uromodulin storage disease regarding renal dysfunction as well as bone, energy and lipid metabolism.
Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism“, Kemter et al., Am J Physiol Renal Physiol. 2009 Nov;297(5):F1391-8.