Rosiglitazone inhibits insulin-like growth factor-1-induced polycystic kidney disease cell growth and p70S6 kinase activation

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders. Thiazolidinediones (TZDs) are anti-diabetic drugs that have been shown to suppress polycystic kidney diseases (PKD) development. However, their underlying mechanism of action remains largely unknown. Insulin-like growth factor-1 (IGF-1) expression increases with the progression of cystic lesions in ADPKD and murine PKD, thus the increased expression of IGF-1 may contribute to the progression of cystic lesions. p70S6 kinase (p70S6K) is an important downstream signaling molecule of IGF-1 and is implicated in the regulation of cell cycle progression and cell proliferation. In the present study, we found that IGF-1 increased the growth of cyst-lining epithelial cells by 15-20% in a dose-dependent manner, while no effect on the proliferation of normal renal cortical tubular epithelial cells (RCTEC) was observed. Rosiglitazone, a TZD, was found to inhibit the IGF-1-induced growth of cyst-lining epithelial cells when applied at a dose of 50-200 μM. However, the IGF-1-induced growth of immortalized epithelial cells from >30 individual renal cysts obtained from 11 ADPKD patients (WT9-12 cells) was inhibited with a 12.5-μM dose of rosiglitazone. Moreover, rosiglitazone (at the same concentration) was shown to inhibit the IGF-1-induced activation of p70S6K. TZDs are known to exert antitumor properties via peroxisome proliferator-activated receptor (PPAR)γ-dependent and -independent mechanisms. The present study showed that PPARγ small interfering RNA (siRNA) did not block the effect of rosiglitazone in inhibiting the IGF-1-induced phosphorylation of p70S6K. In conclusion, cyst-lining epithelial cells were found to be more sensitive to IGF-1 compared with normal cells. Rosiglitazone inhibited the proliferation of cyst-lining epithelial cells; more specifically, it inhibited the proliferation-promoting activity of IGF-1 in these cells. This effect of rosiglitazone was demonstrated to be partially due to the inhibition of IGF-1-induced activation of p70S6K. Increased IGF-1 expression was identified in early-stage PKD, indicating that rosiglitazone is more suitable for the treatment of early-stage PKD.