New Rat Model that Phenotypically Resembles Autosomal Recessive Polycystic Kidney Disease

Abstract

Abstract. 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.