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Effects of a Novel PPARγ Agonist on Cell Proliferation in ADPKD Cystic-lining Epithelial Cells

Author: LiuMoYan
Tutor: MeiChangLin
School: Second Military Medical University
Course: Internal Medicine
Keywords: New PPARγ agonist ADPKD Wnt / β-catenin signaling pathway Apoptosis Cell cycle
CLC: R692.1
Type: Master's thesis
Year: 2009
Downloads: 59
Quote: 0
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Abstract


Objective: inhibit the proliferation of human polycystic kidney cyst lining epithelial cells (WT9-12) based on distribution of β-catenin expression differences observed polycystic kidney tissue; explore new PPARγ agonist DH9; and compare Rosiglitazone study the expression and activation of β-catenin in the cells, and to elucidate its mechanism of action. Methods: Using immunohistochemistry ADPKD patients and ADPKD animal models PKDV / V mouse kidney tissue and corresponding normal kidney tissue distribution and expression of β-catenin differences and to different concentrations DH9 and rosiglitazone WT9 -12 cells 24, 48, 72 and 96 hours after the inhibition of cell proliferation rate was determined by MTT. Use of Western blotting analysis after the DH9 single intervention with GSK3β inhibitor SB216763 proteasome inhibitor MG132 and PPAR-γ inhibitor GW9662 total intervention WT9-12 cells, the intracellular β-catenin phosphorylation of β-catenin, of GSK3β phosphorylation of GSK3β cyclinA the P21 CIP/WAF1, Bax, expression of Bcl-2 protein expression while WT9-12 cells β-catenin mRNA expression by RT-PCR analysis DH9. Dependent on flow cytometry and Annexin V PI double staining and flow cytometry were observed on the cell cycle and apoptosis rate. Results: the distribution of normal kidney tissue tubule cells of β-catenin in cell membrane at the nucleus and cytoplasm rare; renal cyst lining epithelial cells, β-catenin loss of normal characteristics are mainly distributed in the membrane at the replaced cell pulp and Nuclear expression was significantly increased, indicating the presence of nuclear translocation enhancement. The DH9 suppression WT9-12 cell proliferation was significantly better than rosiglitazone (P lt; 0.05), and dose - and time - effect relationship. PPARγ inhibitor GW9662 before and after comparison while adding its inhibitory effect on cell proliferation was no statistically significant difference (P gt; 0.05). DH9 WT9-12 cells, the level of β-catenin mRNA had no significant impact, but down WT9-12 cells, β-catenin protein levels and MG132 and SB216763 intervention can reverse DH9 on WT9-12 β- role of catenin downward. DH9 can increase the P21 CIP/WAF1 protein synthesis, reducing cyclin A protein synthesis, cell cycle arrest in the S phase. DH9 for 72 hours after the Bcl-2 / Bax ratio compared with the control group decreased significantly (P lt; 0.05), indicating that promote apoptosis. Discussion: β-catenin in human and PKDV / V mice polycystic kidney tissue cyst lining epithelial cells express significantly higher than normal tubular epithelial cells, and the presence of nuclear translocation, display abnormal activation of the Wnt / β-catenin signaling pathway . Novel PPARγ agonist the DH9 has suppression WT9-12 cell proliferation activity and its role is significantly better than rosiglitazone statistically significant difference (P lt; 0.05). Through a series of signal transfer protein inhibitor of intervention cultivate cells proved the DH9, and rosiglitazone are presented WT9-12 cell proliferation inhibition by the non-PPARγ dependent pathway, the study also showed that they are reduced by GSK3β-dependent manner β- catenin expression of Wnt / β-catenin signaling pathway inhibition classic block the cell cycle in the S phase and induce apoptosis to achieve its function. The conclusion of our study is novel PPARγ agonist DH9 comparing rosiglitazone to inhibit polycystic kidney cyst lining epithelial cells stronger role; mechanism GSK3β dependent inhibition of Wnt/β- catenin signaling pathway is abnormally activated block cell cycle and promote apoptosis. In this study, the experimental and theoretical basis for the treatment of polycystic kidney disease, has important clinical value and practical significance.

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CLC: > Medicine, health > Surgery > Urology ( urinary and reproductive system diseases) > Kidney disease > Renal malformations
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