An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice

Traykova-Brauch et al . have developed a new approach to modeling renal diseases such as polycystic kidney disease, renal fibrosis and renal cancer in transgenic mice. In contrast to currently available tools, Pax8 -rtTA–transgenic mice have high levels of transgene expression in a highly kidney-specific, uniform and tetracycline–dependent manner. The usefulness of the Pax8 –rtTA system, which is both inducible and reversible, has been shown in three different settings. We describe a transgenic mouse line, Pax8 -rtTA, which, under control of the mouse Pax8 promoter, directs high levels of expression of the reverse tetracycline–dependent transactivator (rtTA) to all proximal and distal tubules and the entire collecting duct system of both embryonic and adult kidneys. Using crosses of Pax8 -rtTA mice with tetracycline-responsive c-MYC mice, we established a new, inducible model of polycystic kidney disease that can mimic adult onset and that shows progression to renal malignant disease. When targeting the expression of transforming growth factor-β1 to the kidney, we avoided early lethality by discontinuous treatment and successfully established an inducible model of renal fibrosis. Finally, a conditional knockout of the gene encoding tuberous sclerosis complex-1 was achieved, which resulted in the early outgrowth of giant polycystic kidneys reminiscent of autosomal recessive polycystic kidney disease. These experiments establish Pax8 -rtTA mice as a powerful tool for modeling renal diseases in transgenic mice.