Familial juvenile hyperuricemic nephropathy (FJHN) and
medullary cystic kidney disease type 2 (
MCKD2) are autosomal dominant disorders characterized by juvenile
hyperuricemia of the underexcretion type,
juvenile gout and
chronic renal failure in the adult. FJHN/
MCKD2 constitute diseases caused by mutations of the human
uromodulin (UMOD) gene that encodes
uromodulin, the most abundant
glycoprotein in normal human urine. The mutations affect the transport of
uromodulin, resulting in the accumulation of
uromodulin in the kidneys of FJHN/
MCKD2 patients. The purpose of this study was to confirm the accumulation of
uromodulin in the kidneys of transgenic mice harboring the mutant human UMOD gene with mouse UMOD gene promoter, and to determine the relationship between its accumulation and the effect on
uromodulin transport. The mutant human UMOD
mRNA and its
protein were expressed in the kidneys of transgenic mice. Moreover, the staining of human
uromodulin was colocalized with that of mouse
uromodulin. Although the human UMOD
mRNA levels increased, the
protein levels did not change and the accumulation of human
uromodulin was not observed. However, the mouse
uromodulin consists of two forms, 103 and 117 kDa, and the 103 kDa
protein was gradually increased in the kidneys of transgenic mice. Human and mouse uromodulins in the kidneys of transgenic mice were mainly detected in the
Triton X-100 insoluble microsomal fraction. Therefore, the progressive accumulation of
uromodulin was observed in the plasma membrane of the kidneys of transgenic mice but the accumulated
uromodulin protein was not that encoded by the transgene.