Kruppel-like Factor-15 Inhibits the Proliferation of Mesangial Cells

Abstract

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.

Benzene and its metabolite decreases cell proliferation via LncRNA-OBFC2A-mediated anti-proliferation effect involving NOTCH1 and KLF15

“…Besides, Konishi J et al showed that inhibition of Notch signaling by a γ-secretase inhibitor suppresses the growth of non-small cell lung cancer (NSCLC) [41]. Accumulating evidence suggests that Notch signaling plays a critical role in the development of several types of cancer, functioning as a tumor promoter [44–52]. NOTCH1 has been shown to be a gene that promotes cell proliferation [53, 54].…”

“…In the human breast cancer-derived cell line T47D, KLF15 has been reported to decrease estrogen-dependent cell proliferation [43]. KLF15 inhibits the proliferation of mesangial cells [44]. Besides, KLF15 suppresses cell proliferation of mesangial cells under high glucose [45] and it negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication [43].…”

Immunosuppressive effects of hydroxychloroquine and artemisinin combination therapy via the nuclear factor‑κB signaling pathway in lupus nephritis mice

“…KLF15 is a key regulator of podocyte differentiation, and a loss of KLF15 increases the susceptibility to kidney injury ( 25 ). KLF15 is highly expressed in the normal endothelial and mesangial cells of the kidney ( 26 ). NF-κB is a downstream target gene of KLF15, and KLF15 affects the downstream cascade reaction by regulating the expression of NF-κB.…”

The critical role of Krüppel-like factors in kidney disease

“…KLF6 expression was induced in cultured glomerular mesangial cells in the setting of sublytic complement-mediated apoptosis (55). In addition, KLF15 expression was reduced in mesangial cells during the proliferative phase of Thy-1 rat model of mesangial glomerulonephritis (21). Interestingly, modulating the expression of KLF15 in cultured mesangial cells inversely regulated the levels of E2F1, cyclin D1, and CDK2 expression.…”