Novel Effect of Chitooligosaccharide on Cyst Growth Retardation in an in vitro Cyst Model of Polycystic Kidney Disease

Abstract

Polycystic kidney disease (PKD) is a common inherited disorder characterized by multiple fluid‐filled cysts that replace normal renal parenchyma along the renal tubules leading to impaired renal function and end‐stage renal disease (ESRD). It has recently been reported that the activation of AMP‐activated protein kinase (AMPK) by metformin inhibits mammalian target of rapamycin (mTOR)‐mediated cell proliferation and cystic fibrosis transmembrane conductance regulator (CFTR)‐mediated chloride secretion in Madin‐Darby canine kidney (MDCK) cell, a cell line derived from distal nephron of dog kidneys. Therefore, AMPK activators are proposed to be a promising agent for PKD treatment. Recently, our research group has shown that chitooligosaccharide (COS) derived from chitin/chitosan activates AMPK in intestinal epithelial cells. This study was conducted based on the hypothesis that AMPK activation by COS may inhibit cyst growth in the in vitro cyst model of PKD. We found that COS at the concentrations of 10, 50, and 100 μg/mL decreased cyst growth in a concentration‐dependent manner without toxicity measured by MTT assays. Immunoblotting analysis showed that COS at 100 μg/mL activated AMPK and this effect was abolished by STO‐609, a calcium/calmodulin‐dependent kinase kinase beta (CaMKKβ) inhibitor. Moreover, COS could elevate the level of intracellular calcium. These results suggest that COS inhibits cyst progression by activation of AMPK and the increment of intracellular calcium level via CaMKKβ. Therefore, COS has novel potential application for the treatment of polycystic kidney disease.Support or Funding InformationFaculty of Medicine Ramathibodi Hospital, Mahidol University