title: 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.
authors.affiliation: Department of Nephrology, The Second Affiliated Hospital of Dalian Medical University, Liaoning 116027, P.R. China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.forename: Lili
authors.initials: L
authors.lastname: Fu
authors.forename: Changlin
authors.initials: C
authors.lastname: Mei
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007684:Kidney Tubules / Q000166:cytology; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D007690:Polycystic Kidney Diseases / Q000378:metabolism / Q000473:pathology; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D007334:Insulin-Like Growth Factor I; D038762:Ribosomal Protein S6 Kinases, 70-kDa