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Placental growth factor gene silencing mitigates the epithelial?to?mesenchymal transition via the p38 MAPK pathway in rats with hyperoxia?induced lung injury.

ABSTRACT: Hyperoxia may cause pulmonary fibrosis in neonates and is characterized by the epithelial?to?mesenchymal transition (EMT) of alveolar epithelial cells. The placental growth factor (PLGF) gene is a member of the vascular endothelial growth factor family and is highly expressed in lung tissues that have been exposed to hyperoxia. The aim of the present study was to assess the role of PLGF in the EMT of lung tissue. Lung tissue exhibiting low PLGF expression was obtained by injecting rats exposed to hyperoxia with a PLGF?silencing lentiviral plasmid. Western blot analysis and immunohistochemistry revealed that expression levels of the EMT?related protein epithelial?cadherin were increased, whereas its inhibitor protein zinc?finger E?box binding homeobox 2 was decreased in these rats. These data demonstrated that PLGF silencing may significantly mitigate hyperoxia?induced EMT in rat lung tissue. Additionally, an increase in phosphorylated?p38 MAPK protein expression indicated that PLGF may be able to regulate hyperoxia?induced lung injury in rats via the p38 MAPK pathway.

SUBMITTER: Zhao S

PROVIDER: S-EPMC6854522 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Placental growth factor gene silencing mitigates the epithelial‑to‑mesenchymal transition via the p38 MAPK pathway in rats with hyperoxia‑induced lung injury.

Zhao Shuang S Luo Gang G Wu Hongmin H Zhang Liang L

Molecular medicine reports 20191030 6

Hyperoxia may cause pulmonary fibrosis in neonates and is characterized by the epithelial‑to‑mesenchymal transition (EMT) of alveolar epithelial cells. The placental growth factor (PLGF) gene is a member of the vascular endothelial growth factor family and is highly expressed in lung tissues that have been exposed to hyperoxia. The aim of the present study was to assess the role of PLGF in the EMT of lung tissue. Lung tissue exhibiting low PLGF expression was obtained by injecting rats exposed t ...[more]

PMID: 31702808

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Project description:BackgroundOur previous study indicated that Ginkgo biloba leaf extract (EGb) could protect against cisplatin-induced acute kidney injury in rabbits. The present study aimed to determine the effects and potential molecular mechanisms of EGb on chronic renal interstitial fibrosis induced by cisplatin using in vivo and in vitro models.MethodsRats received a single dose of cisplatin on Day 1, and a subset of rats was intraperitoneally injected with EGb daily between Days 22-40. In vitro, HK-2 cells were treated with cisplatin, and a subset of cells was cultivated with EGb or SIS3 (Smad3 inhibitor) for 48 h. Renal function of rats was assessed by detecting the levels of serum creatinine (Scr), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG). Hematoxylin and eosin staining and Masson's trichrome staining were used to evaluate the damage and fibrosis of renal tissue. Western blotting, immunohistochemistry and immunofluorescence were used to detect the protein levels of fibrosis-associated proteins and signaling pathway-related proteins. RT-qPCR analysis was used to examine the mRNA levels of related indicators.ResultsEGb significantly decreased the increased levels of Scr, BUN and urinary NAG and attenuated renal damage and the relative area of renal interstitial fibrosis induced by cisplatin. Additionally, EGb decreased the protein levels of α-SMA, Col I, TGF-β1, smad2/3, phosphorylated (p)-smad2/3, p38 MAPK, and p-p38 MAPK; the ratio of p-p38 MAPK/p38 MAPK; and the mRNA level of p38 MAPK in renal tissues induced by cisplatin. In agreement with in vivo studies, EGb significantly reduced the increased protein levels of these indicators. Additionally, EGb significantly reduced the increased protein levels of vimentin, TIMP-1, and CTGF, as well as the mRNA levels of α-SMA, vimentin, and TGF-β1, while it significantly increased the reduced E-cadherin protein level and the MMP-1/TIMP-1 ratio in HK-2 cells induced by cisplatin. It's worth noting that the effects of SIS3 in changing the above indicators were similar to those of EGb.ConclusionOur study demonstrated that EGb improved cisplatin-induced chronic renal interstitial fibrosis, and its mechanisms were associated with inhibiting the epithelial-mesenchymal transition of renal tubular epithelial cells via the Smad3/TGF-β1 and Smad3/p38 MAPK pathways.

Project description:BackgroundEpithelial-mesenchymal transition of tubular epithelial cells, which is characterized by a loss of epithelial cell characteristics and a gain of ECM-producing myofibroblast characteristics, is an essential mechanism that is involved in tubulointerstitial fibrosis, an important component of the renal injury that is associated with diabetic nephropathy. Under diabetic conditions, p38 MAPK activation has been reported in glomeruli and mesangial cells; however, studies on p38 MAPK in TECs are lacking. In this study, the role of p38 MAPK in AP-1 activation and in the EMT in the human proximal tubular epithelial cell line (HK-2) under high glucose concentration conditions is investigated.Methodology/principal findingsA vector for small interfering RNA that targets p38 MAPK was constructed; the cells were then either transfected with p38 siRNA or pretreated with a chemical inhibitor of AP-1 and incubated with low glucose plus TGF-β1 or high glucose for 48 h. Cells that were not transfected or pretreated and were exposed to low glucose with or without TGF-β1 or high glucose for 48 h were considered to be the controls. We found that high glucose induced an increase in TGF-β1. And high glucose-induced p38 MAPK activation was inhibited by p38 siRNA (P<0.05). A significant decline in E-cadherin and CK expression and a notable increase in vimentin and α-SMA were detected when exposed to low glucose with TGF-β1 or high glucose, and a significant raise of secreted fibronectin were detected when exposed to high glucose; whereas these changes were reversed when the cells were treated with p38 siRNA or AP-1 inhibitor (P<0.05). AP-1 activity levels and Snail expression were up-regulated under high glucose conditions but were markedly down-regulated through knockdown of p38 MAPK with p38 siRNA or pretreatment with AP-1 inhibitor (P<0.05).ConclusionThis study suggests that p38 MAPK may play an important role in the high glucose-induced EMT by activating AP-1 in tubular epithelial cells.

Dataset Information

Placental growth factor gene silencing mitigates the epithelial?to?mesenchymal transition via the p38 MAPK pathway in rats with hyperoxia?induced lung injury.

Publications

Placental growth factor gene silencing mitigates the epithelial‑to‑mesenchymal transition via the p38 MAPK pathway in rats with hyperoxia‑induced lung injury.

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