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Dr. Yan Zhang 
Postdoctoral Fellow
Jared Grantham Kidney Institute
University of Kansas-Medical Center 

Presentation Title: Targeting mTOR upstream regulators in Autosomal Dominant Polycystic Kidney Disease 

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disorder with a frequency of 1:500 individuals and accounts for 7~9% of patients on renal replacement therapy. ADPKD is characterized by aberrant cells proliferation and Cl--dependent fluid secretion resulting in the formation and growth of fluid-filled cysts, massively enlarged kidneys and progressive decline in renal function. Currently, there is no cure for ADPKD, and treatment options are limited. In ADPKD, mammalian Target Of Rapamycin (mTOR) signaling is hyperactivated and contributes to cell proliferation; cystic fibrosis transmembrane conductance regulator (CFTR), a Cl- channel, mediates fluid secretion within the cyst cavity. AMP-activated protein kinase (AMPK), primarily activated by liver kinase B1 (LKB1), is an important negative regulator of both mTOR and CFTR. Currently, the role of LKB1-AMPK signaling pathway is poorly understood in the progression of PKD. Our studies showed that LKB1/AMPK signaling was dysregulated in human ADPKD cells. LKB1 knockout accelerated cyst growth and renal fibrosis in ADPKD mouse model. A novel LKB1 activator BIT-11, which potently activated AMPK in nanomolar concentrations, inhibited mTOR-mediated cell proliferation and Cl- secretion in human ADPKD cells. BIT-11 also decreased the cyst growth and PKD progression in PKD mice. In addition, we identified calcium/calmodulin-dependent kinase type IV (CaMK4) is a novel regulator of mTOR in human ADPKD cells. We found CaMK4 expression was elevated in human ADPKD and PKD mice; inhibition or knockdown CaMK4 remarkably decreased mTOR signaling in human ADPKD cells. Our studies show that targeting mTOR upstream regulators are potential novel therapeutic approaches for human ADPKD treatment.