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Kruppel-like factor-15 inhibits the proliferation of mesangial cells
Quan Hong1, Cui Li, Yuansheng Xie
1State Key Laboratory of Kidney Disease, Institute of Nephrology, Chinese PLA General Hospital, Beijing, China.
Background/Aims:
The Kruppel-like factor-15 (KLF15), a DNA-binding transcription factor, is highly expressed in endothelial and mesangial cells of the kidney. However, its effects on mesangial cell proliferation have not previously been investigated. In this study, we investigated the effect of KLF15 on mesangial cell proliferation.
Methods:
We established a classic rat anti-Thy1 mesangial proliferative nephritis model. Affymetrix rat U230 2.0 chip was used to detect the gene expression profiles at different time point in the model. The different expression of KLF15 was shown during mesangial cell proliferation period and proliferation declined period of anti-Thy1 nephritis model by microarray analysis, Real-time PCR and Western blotting. Then we determined the effects of KLF15 and its downstream target, cell cycle regulation factor E2F1 on the proliferation of mesangial cells and the expression of the positive-acting cell cycle regulatory proteins, cyclinD1 and CDK2, by means of positive and negative interference experiments in cultured rat mesangial cells. We detected also protein expression of E2F1, cyclinD1 and CDK2 in vivo.
Results:
By real-time PCR, Western blotting, and microarray analysis, KLF15 expression was shown to be lower during mesangial cell proliferation period and higher during proliferation declined period and under normal conditions. The mesangial cell proliferation was reduced and the expression of E2F1, cyclin D1 and CDK2 was downregulated in mesangial cells overexpressing KLF15. When KLF15 expression was inhibited by siRNA, the expression of E2F1, cyclin D1 and CDK2 and mesangial cell proliferation were increased. When E2F1 was inhibited by siRNA, protein level of CDK2 and cyclin D1 were lower than control. When siE2F1 was co-transfected with siKLF15 into mesangial cells, the increase of cell proliferation induced by siKLF15 was eliminated partly by siE2F1. Moreover, E2F1, cyclin D1 and CDK2 were higher expression during mesangial cell proliferation period, and were downregulated during proliferation declined period in vivo.
Conclusions:
These results suggest that KLF15 inhibits mesangial cell proliferation, possibly by regulating the expression of cell cycle regulation proteins through E2F1. Thus, KLF15 may be a useful target for therapeutic intervention in mesangial proliferative glomerulonephritis.
Insights
Kruppel-like factor-15 (KLF15) inhibits kidney mesangial cell proliferation by regulating cell cycle proteins. KLF15 may be a therapeutic target for mesangial proliferative glomerulonephritis.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Kruppel-like factor-15 (KLF15) is a transcription factor highly expressed in kidney cells.
- Its role in mesangial cell proliferation was previously uninvestigated.
Purpose of the Study:
- To investigate the effect of KLF15 on mesangial cell proliferation.
- To elucidate the underlying molecular mechanisms involving E2F1 and cell cycle proteins.
Main Methods:
- Established a rat anti-Thy1 nephritis model to study mesangial proliferative nephritis.
- Utilized microarray analysis, Real-time PCR, and Western blotting to assess gene and protein expression.
- Performed in vitro experiments with cultured rat mesangial cells using positive and negative interference (siRNA) for KLF15 and E2F1.
Main Results:
- KLF15 expression was inversely correlated with mesangial cell proliferation.
- Overexpression of KLF15 reduced mesangial cell proliferation and downregulated E2F1, cyclin D1, and CDK2.
- Inhibition of KLF15 increased proliferation and E2F1, cyclin D1, and CDK2 expression, effects partially reversed by E2F1 inhibition.
Conclusions:
- KLF15 inhibits mesangial cell proliferation, likely via regulation of E2F1 and associated cell cycle proteins.
- KLF15 represents a potential therapeutic target for mesangial proliferative glomerulonephritis.
