Effects of Pkd1 inactivation defined by important developmental switch in post-natal kidney maturation. Mus musculus

Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of end stage renal disease for which there is no proven therapy 1. Mutations at PKD1 are the principal cause of disease. The disease begins in utero2 and is slowly progressive but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice prior to post-natal day 13 results in severely cystic kidneys within three weeks, whereas inactivation at day 14 and later results in cysts only after five months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls but that the abrupt change in response to Pkd1 inactivation corresponded with a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. These studies show that Pkd1 regulates tubular morphology in both developing and adult kidney but the pathologic consequences of inactivation are defined by the organ’s developmental status, with important clinical implications for our understanding of disease and our approach to therapy. Keywords: Developmental status comparison Overall design: Goal: Analyze differences in gene expression during late stages of post-natal kidney maturation (i.e. P11, P12, P14 and P15). Paper: Klaus Piontek, Luis F. Menezes, Miguel Garcia-Gonzalez, David L. Huso, Gregory G. Germino. Effects of Pkd1 inactivation defined by major developmental switch in post-natal kidney maturation. Design: Kidneys were harvested from wild-type mice at post-natal days 11,12,14 and 15. Four animals (one kidney/animal) and two technical replicates per time point were used.