mTORC1-mediated growth of kidney cysts is rapidly bypassed by other signaling pathways

Cystic kidney disease (CyKD) is the leading monogenetic cause of endstage renal disease. In both mice and humans CyKD has been consistently linked to the activation of the mTORC1 pathway. Yet, the utility of mTORC1 inhibitors in CyKD patients remains controversial despite promising preclinical data. To conclusively define the cell intrinsic role of mTORC1 for cyst development, mTORC1 was selectively inactivated in renal tubular cells of an aciliary mouse model of CyKD by deleting the decisive scaffolding protein RAPTOR. Initial preservation of renal function in CyKD∆RAP mice was followed by a steady decline in renal function coinciding with the development of renal cysts in these animals. While overall survival in CyKD∆RAP was considerably prolonged, in-depth transcriptomic analysis showed a rapid activation of other growth-promoting pathways, limiting the effects of mTORC1 deficiency to a relatively small therapeutic window. Future trials in patients with polycystic kidney disease need to acknowledge these findings, and might have to consider combinatorial or sequential therapies to improve efficacy. Raptor fl/fl or Kif fl/fl mice (used as Control), Raptor fl/fl*KspCre, Kif3a fl/fl*KspCre and Raptor fl/fl*Kif3a fl/fl*KspCre animals were sacrificed at 1 day, 1, 2 and 4 weeks (n>=7). Kidneys were split in half and immediately snap frozen in liquid nitrogen. RNA was purified using standard procedures and analyzed using Affimetrix Mouse Genome 430 2.0 gene chips.