Transgenic Overexpression of Anks6(p R823W) Causes Polycystic Kidney Disease in Rats

The PKD/Mhm(cy/+) rat is a widely used animal model for the study of human autosomal dominant polycystic kidney disease one of the most common genetic disorders affecting one in 1000 individuals We identified a new gene Anks6 which is mutated (Anks6((p R823W))) m PKD/Mhm(cy/+) rats The evidence for a causal link between Anks6((p R823W)) and cystogenesis is still lacking, and the function of Anks6 is presently unknown This study presents a novel transgenic rat model that overexpresses the mutated 2 8 kb Anks6((p R823W)) cDNA m the renal tubular epithelium The transgenic Anks6((p R823W)) acts in a dominant negative fashion and causes a predictable poly cystic phenotype that largely mimics the general characteristics of the PKD/Mhm(cy/+) rats Cyst development is accompanied by enhanced c myc expression and continuous proliferation apoptosis and de differentiation of the renal tubular epithelium as well as by a lack of translational up regulation of p21 during aging Using Northern blot analysis and in situ hybridization studies we identified the first 10 days of age as the period during which transgene expression precedes and initiates cystic growth Thus we not only provide the first in vivo evidence for a causal link between the novel Anks6((p R823W)) gene mutation and polycystic kidney disease but we also developed a new transgenic rat model that will serve as an important resource for further exploration of the still unknown function of Anks6 (Am J Pathol 2010 177 3000-3009 DOI 10 2353/ajpath 2010 100569)