The jck murine model, which results from a double point mutation in the nek8 gene, has been used to study the mechanism of
autosomal recessive polycystic kidney disease (
ARPKD). The renal
proteome of jck mice was characterized by two-dimensional gel electrophoresis combined with mass spectrometry (MALDI-TOF/TOF). Four newly identified
proteins were found to accumulate in the kidneys of jck mice with
polycystic kidney disease (PKD) compared with their wild-type littermates. The
proteins galectin-1, sorcin, and
vimentin were found to be induced 9-, 9-, and 25-fold, respectively, in the PKD
proteome relative to the wild type. The identity of these
proteins was established by
peptide mass fingerprinting and de novo MS/MS sequencing of selected
peptides. Up-regulation of these three
proteins may be due to the nek8 mutation, and their function may be related to the signaling and structural processes in the primary cilium. Additionally a series of
protein isoforms observed only in the
ARPKD kidney was identified as the major urinary
protein (MUP).
Peptide sequencing demonstrated that the
isoforms MUP1, MUP2, and MUP6 are contained in this series. The MUP series showed a number of male-specific
isoforms and a phosphorylation of the entire series with an increasing degree of phosphorylation of the acidic
isoforms. In addition, the MUP series was localized to the cyst fluid of PKD mice, and a cellular mislocalization of
galectin-1, sorcin, and
vimentin in PKD tubular epithelial cells was shown. The abnormal and extremely high accumulation of the MUPs in the
ARPKD kidney may be linked to a defect in protein transport and secretion. The discovery of these
proteins will provide new information on the molecular and cellular processes associated with the mechanism of
ARPKD.