Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent, inherited condition for which there is currently no effective specific clinical therapy. The disease is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells which gradually compress the parenchyma and compromise renal function. Current interests in the field focus on understanding and exploiting signaling pathways underlying disease pathogenesis as well as delineating the role of the primary cilium in cystogenesis. The goals of our present studies parallel these interests.

At the cellular level, renal cyst development and expansion in ADPKD are hypothesized to result from two disparate processes: increased fluid secretion into the cyst lumen and abnormal proliferation of cyst-lining epithelial cells. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel participates in the secretion of cyst fluid, while the mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial cells. Interestingly, both the CFTR chloride channel and the mTOR signaling pathway are negatively regulated by the "energy sensing" molecule, Adenosine Monophosphate activated Protein Kinase (AMPK).

Metformin, an FDA-approved drug in wide clinical use, is a pharmacological activator of AMPK. We find that metformin stimulates AMPK, resulting in inhibition of both the CFTR and the mTOR pathways and thereby, both epithelial secretion and proliferation, respectively. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo models of renal cystogenesis. Moreover, metformin administration produces a significant decrease in cystic index in two severe mouse models of ADPKD. Thus, AMPK emerges as a valuable and novel target for pharmacotherapy with the potential for therapeutic trials of metformin in ADPKD patients.

At the level of an individual cell, understanding primary cilium formation and maintenance has provided insight into cyst formation. In rodent models of PKD, ciliary proteins or proteins which regulate ciliary transport are often perturbed, with ensuing cystogenesis. Mice overexpressing vesicle integral protein of 17 kDa (VIP17) develop large cysts. Our studies therefore also investigate the role of overexpression of VIP17 on cilia formation both in vitro and in vivo. We find that in both cases ciliary length and morphology is abnormal relative to controls.

In summary, we present original data demonstrating a signaling pathway that may be exploited for therapeutic benefit in PKD as well as preliminary studies evaluating ciliogenesis in another model of renal cystic disease.