Because
proteinuria has been demonstrated in patients with
autosomal-dominant polycystic kidney disease (
ADPKD), we have investigated whether
proteinuria also occurs in the (cy/+) rat, a widely used model for
ADPKD. Increased urinary excretion of
proteins, in particular of
albumin, can be found in 16-wk-old (cy/+) rats, with a gel electrophoresis pattern compatible with a tubular origin of
proteinuria. Using
FITC-labeled
dextran as an in vivo tracer for renal tubular endosomal function, we could show that portions of
cyst-lining epithelia from proximal tubules have lost the ability to endocytose, which is necessary for the reabsorption of low-molecular-weight
proteins. By immunohistochemistry, the expression of other
proteins implicated in endocytosis, such as the
chloride channel ClC-5 and the
albumin receptor megalin, correlated well with the presence and absence of
FITC-dextran in
cysts. As an example of
growth factor systems possibly being affected by this endocytosis defect, we could detect increased urinary levels of
insulin-like growth factor-I protein in (cy/+) animals. These data indicate that
proteinuria and
albuminuria in the aforementioned rat model for
ADPKD are due to a loss of the endocytic machinery in epithelia of proximal tubular
cysts. This may also affect the concentration of different
growth factors and
hormones in cyst fluids and thus modulate
cyst development.