Numerous murine models of polycystic kidney disease (PKD) have been
described. While mouse models are particularly well suited for
investigating the molecular pathogenesis of PKD, rats are well established
as an experimental model of renal physiologic processes. Han:SPRD-CY: rats
have been proposed as a model for human autosomal dominant PKD. A new
spontaneous rat mutation, designated wpk, has now been identified. In the
mutants, the renal cystic phenotype resembles human autosomal recessive
PKD (ARPKD). This study was designed to characterize the clinical and
histopathologic features of wpk/wpk mutants and to map the wpk locus.
Homozygous mutants developed nephromegaly, hypertension, proteinuria,
impaired urine-concentrating capacity, and uremia, resulting in death at 4
wk of age. Early cysts were present in the nephrogenic zone at embryonic
day 19. These were localized, by specific staining and electron
microscopy, to differentiated proximal tubules, thick limbs, distal
tubules, and collecting ducts. In later stages, the cysts were largely
confined to collecting ducts. Although the renal histopathologic features
are strikingly similar to those of human ARPKD, wpk/wpk mutants exhibited
no evidence of biliary tract abnormalities. The wpk locus maps just
proximal to the CY: locus on rat chromosome 5, and complementation studies
demonstrated that these loci are not allelic. It is concluded that the
clinical and renal histopathologic features of this new rat model strongly
resemble those of human ARPKD. Although homology mapping indicates that
rat wpk and human ARPKD involve distinct genes, this new rat mutation
provides an excellent experimental model to study the molecular
pathogenesis and renal pathophysiologic features of recessive PKD