Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disease, affecting at least 600,000 Americans. It is characterized by massive cystic growth and enlargement of the kidneys, ultimately progressing to renal failure. There are currently no FDA-approved pharmaceutical therapies for ADPKD. Renal cyst formation is attributed to both excess apical fluid secretion into the cyst lumen and inappropriate proliferation of the renal epithelial cells. These processes are thought to be mediated by the CFTR chloride channel and the mTOR pathway, respectively. Both of these targets lie downstream of and are antagonized by Adenosine Monophosphate-activated Protein Kinase (AMPK). Previous therapies have been targeted to address one or the other of these two processes. We hypothesize that if AMPK is stimulated, then this will further the inhibition of both CFTR and mTOR, leading to decreased cystogenesis. This study will seek to exploit the activity of AMPK to further inhibit the abnormal secretion and proliferation observed in renal cystic disease with the following Aims: (1.) Characterize the effects of AMPK stimulation on its downstream targets in renal epithelia, and (2.) Evaluate the in vitro and in vivo effects of metformin-induced AMPK inhibition of mTOR and CFTR in the context of cystic kidney disease. These studies will not only further the understanding the role of AMPK in the pathogenesis of PKD, but also have the potential for clinical application as metformin, a pharmacological activator of AMPK is already FDA approved for the treatment of other conditions, is relatively inexpensive, and has low toxicity. Polycystic kidney disease is a common inherited disease in which patients born with normal kidneys develop large fluid filled cysts that destroy the normal kidney. There are currently no approved medications for this condition, just dialysis. This research project is aimed at developing a drug therapy for polycystic kidney disease, and giving these patients another option.
| Takiar, Vinita; Mistry, Kavita; Carmosino, Monica et al. (2012) VIP17/MAL expression modulates epithelial cyst formation and ciliogenesis. Am J Physiol Cell Physiol 303:C862-71 |
| Takiar, Vinita; Nishio, Saori; Seo-Mayer, Patricia et al. (2011) Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci U S A 108:2462-7 |
