Cyst enlargement in
autosomal dominant polycystic kidney disease (
ADPKD) is associated with cAMP-activated proliferation of
cyst-lining epithelial cells and transepithelial fluid secretion into the
cyst lumen via
cystic fibrosis transmembrane conductance regulator (CFTR)
chloride channel leading to
renal failure for which no effective treatment is currently available. We previously reported that
steviol retards Madin-Darby canine kidney (MDCK)
cyst enlargement by inhibiting CFTR channel activity and promoting proteasomal-mediated CFTR degradation. It is imperative to examine the effect of
steviol in animal models of
ADPKD. Therefore, we examined the effect of
steviol on renal
cyst growth in an orthologous mouse model of human
ADPKD (Pkd1(flox/flox):Pkhd1-Cre). The results showed that daily treatment with both 200mg/kg BW of
steviol and 1000mg/kg BW of
stevioside for 14 days markedly decreased kidney weight and cystic index in these mice. However, only
steviol markedly reduced blood
urea nitrogen and
creatinine values.
Steviol also reduced cell proliferation but had no effect on cell apoptosis. In addition,
steviol suppressed CFTR and mTOR/S6K expression in renal
cyst-lining epithelial cells. Interestingly,
steviol was found to stimulate
AMP-activated protein kinase (AMPK). Our findings indicate that
steviol slows
cyst progression in
ADPKD mouse model, in part, through the activation of AMPK which subsequently inhibits CFTR
chloride channel expression and inhibits renal epithelial cell proliferation via mTOR/S6K pathway. Most importantly,
steviol could markedly improve kidney function in a mouse model of
ADPKD.
Steviol thus has potential application for further development as a therapeutic compound for the treatment of
polycystic kidney disease.