The p70S6K/PI3K/MAPK feedback loop releases the inhibition effect of high-dose rapamycin on rat mesangial cell proliferation
| Autor: | Jihua Tian, Jing Kang, Taiping Huang, Yanhong Wang, Sijia Chang, He Ji, Yun Zhou, Haixiu Guo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Glomerular Mesangial Cell mesangial cell Immunology 030232 urology & nephrology Cell Line 03 medical and health sciences Phosphatidylinositol 3-Kinases 0302 clinical medicine P70S6 kinase Immunology and Allergy Animals Original Research Article p70S6K/PI3K/MAPK Inhibitory effect Glomerular diseases PI3K/AKT/mTOR pathway Cell Proliferation Pharmacology Sirolimus Mesangial cell Chemistry rapamycin Cell Cycle Ribosomal Protein S6 Kinases 70-kDa Rats 030104 developmental biology Mesangial cell proliferation Mesangial Cells Cancer research feedback loop Mitogen-Activated Protein Kinases Proto-Oncogene Proteins c-akt |
| Zdroj: | International Journal of Immunopathology and Pharmacology |
| ISSN: | 2058-7384 0394-6320 |
| Popis: | Glomerular mesangial cell (MC) proliferation is one of the causative factors of glomerular diseases and one of their prominent pathological features. Rapamycin can inhibit MC proliferation and slow the progression to chronic renal fibrosis. The present study was designed to observe the role of rapamycin in MC proliferation and to explore the mechanism by which rapamycin acts on Akt and MAPK/ERK1/2 pathways in mesangial cells. MTT assay and flow cytometry were used to evaluate the proliferation and the cell cycle phase of glomerular mesangial cells respectively. The mRNA expression level of p70S6K was detected by RT-qPCR. Western blotting was performed to determine p70S6K, PI3K/Akt, and PI3K/MAPK protein expression. We found that rapamycin could reduce mesangial cell proliferation and arrest the cell cycle in the G1 phase, however the inhibition effect of 1000 nmol/L rapamycin was not higher than that in the 100 nmol/L group. The results of western blotting showed that 1000 nmol/L rapamycin more significantly inhibited the phosphorylation of p70S6K than 100 nmol/L, suggesting there should be another signaling pathway that activates the proliferation of MCs. Moreover, our results revealed that 1000 nmol/L rapamycin led to Raf1-MEK1/2-ERK pathway activation through a p70S6K-PI3K-mediated feedback loop in MCs. This study demonstrated that high-dose rapamycin leads to ERK1/2 activation through a p70S6K/PI3K/MAPK feedback loop in rat MCs, thus reducing the inhibitory effect of rapamycin on MC proliferation. |
| Databáze: | OpenAIRE |
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