Loss of Fnip1 Results in Renal Cyst Formation and Synergizes with TSC1 Loss to Promote mTORC1 Activation
Centini, Ryan Michael
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Birt-Hogg-Dube’ Syndrome (BHDS) is a rare genetic disorder in humans characterized by increased risk for renal tumors. BHDS is caused by mutations in the BHD gene, which encodes for Folliculin, and cytoplasmic adapter protein which binds to two other proteins called FNIP1 and FNIP2 (Folliculin interacting proteins-1 and -2) as well as AMP kinase (AMPK). AMPK is an important energy sensor for the cell, and once activated stimulates energy production while inhibiting mTOR. Whereas kidney-specific deletion of the Bhd gene in mice is known to result in polycystic kidney disease and renal cell carcinoma, the roles of Fnip1 in renal cell development and function are unclear. In this study, we utilized mice with constitutive deletion of the Fnip1 gene to show that the loss of Fnip1 alone is sufficient to cause a polycystic kidney disease, which was characterized by increased mTOR activation and metabolic hyperactivation. In addition, we found that loss of Fnip1 alone resulted in many cellular and molecular changes previously suggested as contributing to the development of PKD in humans, including alterations in ion channels and amino acid transporters, increased cell adhesion, and increased inflammation. Our results collectively define a novel role of Fnip1 in regulating kidney development and function, and provide a model for how Fnip1 regulates renal cell function.