Steviol retards renal cyst growth through reduction of CFTR expression and inhibition of epithelial cell proliferation in a mouse model of polycystic kidney disease

• Published in: Biochemical pharmacology 2014-04, Vol.88 (3), p.412-421
• Main Authors: Yuajit, Chaowalit, Muanprasat, Chatchai, Gallagher, Anna-Rachel, Fedeles, Sorin V., Kittayaruksakul, Suticha, Homvisasevongsa, Sureeporn, Somlo, Stefan, Chatsudthipong, Varanuj
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Apoptosis; Cell Proliferation; CFTR; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Diterpenes, Kaurane - pharmacology; Diterpenes, Kaurane - therapeutic use; Enzyme Activation; Epithelial Cells - drug effects; Epithelial Cells - pathology; Glucosides - pharmacology; Glucosides - therapeutic use; Humans; Mice; Mice, Mutant Strains; mTOR; Polycystic Kidney Diseases - drug therapy; Polycystic Kidney Diseases - metabolism; Polycystic Kidney Diseases - pathology; Renal cystogenesis; Steviol
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2014.01.038

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 (Pkd1flox/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.