Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1.

Polycystic kidney disease is a disorder of renal epithelial growth and differentiation. Transcription factor EB (TFEB), a master regulator of lysosome biogenesis and function, was studied for a potential role in this disorder. The nuclear translocation and functional responses to TFEB activation were studied in three murine models of renal cystic disease, including knockouts of folliculin, folliculin interacting proteins 1 and 2, and Pkd1 as well as in mouse embryonic fibroblasts lacking Pkd1 and 3-dimensional cultures of MDCK cells. Nuclear translocation of Tfeb characterized cystic but not non-cystic renal tubular epithelia in all three murine models as both an early and sustained response to cyst formation. The epithelia expressed elevated levels of Tfeb-dependent gene products, including cathepsin B and Gpnmb. Nuclear Tfeb translocation was observed in mouse embryonic fibroblasts lacking Pkd1, but not wild type fibroblasts. Pkd1 knockout fibroblasts were characterized by increased Tfeb dependent transcripts, lysosomal biogenesis and repositioning, and increased autophagy. The growth of MDCK cell cysts was markedly increased following exposure to the TFEB agonist, compound C1, and nuclear Tfeb translocation was observed in response to both forskolin and compound C1 treatment. Nuclear TFEB also characterized the cystic epithelia but not non-cystic tubular epithelia in human ADPKD patients. The non-canonical activation of TFEB is characteristic of cystic epithelia in multiple models of renal cystic disease including those associated with the loss of Pkd1. Nuclear TFEB translocation is functionally active in these models and may be a component of a general pathway contributing to cystogenesis and growth.