Transgenic overexpression of prothymosin α induces development of polycystic kidney disease1

Transgenic overexpression of prothymosin α induces development of polycystic kidney disease.BackgroundPolycystic kidney disease (PKD) is a genetic disorder characterized by development of renal cysts and progressive renal dysfunction. Renal tissues from both PKD patients and rodent models of PKD show elevated c-myc expression. Prothymosin α (ProT) is positively regulated by c-myc through binding to the E box of its promoter. Through creating transgenic mice and clinical studies, we sought to investigate whether ProT overexpression contributes to PKD development.MethodsProT heterozygous and homozygous transgenic mice were generated and characterized. Morphologic, histologic, immunohistochemical, and biochemical analyses of the transgenic mice were performed.ResultsTwo transgenic lines that represented integration at two different loci of the chromosomes were generated. ProT overexpression in the kidneys of homozygous transgenic mice induced a PKD phenotype, which included polycystic kidneys, elevated blood urea nitrogen (BUN), and lethality at about 10 days of age. Similar overexpression pattern of ProT was noted in cystic kidneys of the transgenic mice as well as in human autosomal-recessive PKD (ARPKD) and autosomal-dominant PKD (ADPKD) kidneys. ProT protein levels in the kidneys and urine as well as renal mRNA level of epithelial growth factor receptor (EGFR) of homozygous ProT transgenic mice were significantly higher than heterozygous or nontransgenic littermates. Furthermore, the heterozygous transgenic mice at 17 months of age also developed mild cystic kidneys.ConclusionTransgenic mice overexpressing ProT represent a novel model for PKD and may provide insights into PKD development. ProT, like c-myc and EGFR, may contribute to the development of renal cysts and may be a potential noninvasive diagnostic molecule of PKD.