Sp1 mediated the inhibitory effect of glutamate on pulmonary surfactant synthesis.

Autor: Li XH; Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China., Fu JJ; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Shi XJ; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Zhang YN; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Shao M; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Yue SJ; Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China., Li C; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.; Department of Physiology, Changzhi Medical College, Changzhi, Shanxi, China., Luo ZQ; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Aug 09; Vol. 18 (8), pp. e0289530. Date of Electronic Publication: 2023 Aug 09 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0289530
Abstrakt: Background: Studies have shown that the release of endogenous glutamate (Glu) participates in lung injury by activating N-methyl-D-aspartate receptor (NMDAR), but the mechanism is still unclear. This study was to investigate the effects and related mechanisms of Glu on the lipid synthesis of pulmonary surfactant (PS) in isolated rat lung tissues.
Methods: The cultured lung tissues of adult SD rats were treated with Glu. The amount of [3H]-choline incorporation into phosphatidylcholine (PC) was detected. RT-PCR and Western blot were used to detect the changes of mRNA and protein expression of cytidine triphosphate: phosphocholine cytidylyltransferase alpha (CCTα), a key regulatory enzyme in PC biosynthesis. Western blot was used to detect the expression of NMDAR1, which is a functional subunit of NMDAR. Specific protein 1 (Sp1) expression plasmids were used. After transfected with Sp1 expression plasmids, the mRNA and protein levels of CCTα were detected by RT-PCR and Western blot in A549 cells. After treated with NMDA and MK-801, the mRNA and protein levels of Sp1 were detected by RT-PCR and Western blot in A549 cells.
Results: Glu decreased the incorporation of [3H]-choline into PC in a concentration- and time- dependent manner. Glu treatment significantly reduced the mRNA and protein levels of CCTα in lungs. Glu treatment up-regulated NMDAR1 protein expression, and the NMDAR blocker MK-801 could partially reverse the reduction of [3H]-choline incorporation induced by Glu (10-4 mol/L) in lungs. After transfected with Sp1 plasmid for 30 h, the mRNA and protein expression levels of CCTα were increased and the protein expression of Sp1 was also up-regulated. After A549 cells were treated with NMDA, the level of Sp1 mRNA did not change significantly, but the expression of nucleus protein in Sp1 was significantly decreased, while the expression of cytoplasmic protein was significantly increased. However, MK-801could reverse these changes.
Conclusions: Glu reduced the biosynthesis of the main lipid PC in PS and inhibited CCTα expression by activating NMDAR, which were mediated by the inhibition of the nuclear translocation of Sp1 and the promoter activity of CCTα. In conclusion, NMDAR-mediated Glu toxicity leading to impaired PS synthesis may be a potential pathogenesis of lung injury.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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