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

Liu,Chunyan; Zhang,Yi; Yuan,Li; Fu,Lili; Mei,Changlin

doi:10.3892/mmr.2013.1588

September 2013 Volume 8 Issue 3

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September 2013 Volume 8 Issue 3

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Article

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

Authors:
- Chunyan Liu
- Yi Zhang
- Li Yuan
- Lili Fu
- Changlin Mei
View Affiliations / Copyright

Affiliations: Department of Nephrology, The Second Affiliated Hospital of Dalian Medical University, Liaoning 116027, P.R. China, Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
Pages: 861-864
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Published online on: July 16, 2013

https://doi.org/10.3892/mmr.2013.1588
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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.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

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