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Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway.

ABSTRACT: Intrauterine growth retardation (IUGR) impairs fetal intestinal development, and is associated with high perinatal morbidity and mortality. However, the mechanism underlying this intestinal injury is largely unknown. We aimed to investigate this mechanism through analysis of intestinal autophagy and related signaling pathways in a rat model of IUGR. Normal weight (NW) and IUGR fetuses were obtained from primiparous rats via ad libitum food intake and 50% food restriction, respectively. Maternal serum parameters, fetal body weight, organ weights, and fetal blood glucose were determined. Intestinal apoptosis, autophagy, and the mechanistic target of rapamycin (mTOR) signaling pathway were analyzed. The results indicated that maternal 50% food restriction reduced maternal serum glucose, bilirubin, and total cholesterol and produced IUGR fetuses, which had decreased body weight; blood glucose; and weights of the small intestine, stomach, spleen, pancreas, and kidney. Decreased Bcl-2 and increased Casp9 mRNA expression was observed in IUGR fetal intestines. Analysis of intestinal autophagy showed that the mRNA expression of WIPI1, MAP1LC3B, Atg5, and Atg14 was also increased, while the protein levels of p62 were decreased in IUGR fetuses. Compared to NW fetuses, IUGR fetuses showed decreased mTOR protein levels and enhanced mRNA expression of ULK1 and Beclin1 in the small intestine. In summary, the results indicated that maternal 50% food restriction on gestational days 10-21 reduced maternal serum glucose, bilirubin, and total cholesterol contents, and produced IUGR fetuses that had low blood glucose and reduced small intestine weight. Intestinal injury of IUGR fetuses caused by maternal food restriction might be due to enhanced apoptosis and autophagy via the mTOR signaling pathway.

SUBMITTER: Wang C

PROVIDER: S-EPMC5735265 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway.

Wang Chao C Zhang Ruiming R Zhou Le L He Jintian J Huang Qiang Q Siyal Farman A FA Zhang Lili L Zhong Xiang X Wang Tian T

The Journal of reproduction and development 20170831 6

Intrauterine growth retardation (IUGR) impairs fetal intestinal development, and is associated with high perinatal morbidity and mortality. However, the mechanism underlying this intestinal injury is largely unknown. We aimed to investigate this mechanism through analysis of intestinal autophagy and related signaling pathways in a rat model of IUGR. Normal weight (NW) and IUGR fetuses were obtained from primiparous rats via ad libitum food intake and 50% food restriction, respectively. Maternal ...[more]

PMID: 28855439

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Project description:Pro-inflammatory immune system development, metabolomic defects, and deregulation of autophagy play interconnected roles in driving the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis (LN) is a leading cause of morbidity and mortality in SLE. While the causes of SLE have not been clearly delineated, skewing of T and B cell differentiation, activation of antigen-presenting cells, production of antinuclear autoantibodies and pro-inflammatory cytokines are known to contribute to disease development. Underlying this process are defects in autophagy and mitophagy that cause the accumulation of oxidative stress-generating mitochondria which promote necrotic cell death. Autophagy is generally inhibited by the activation of the mammalian target of rapamycin (mTOR), a large protein kinase that underlies abnormal immune cell lineage specification in SLE. Importantly, several autophagy-regulating genes, including ATG5 and ATG7, as well as mitophagy-regulating HRES-1/Rab4A have been linked to lupus susceptibility and molecular pathogenesis. Moreover, genetically-driven mTOR activation has been associated with fulminant lupus nephritis. mTOR activation and diminished autophagy promote the expansion of pro-inflammatory Th17, Tfh and CD3+CD4-CD8- double-negative (DN) T cells at the expense of CD8+ effector memory T cells and CD4+ regulatory T cells (Tregs). mTOR activation and aberrant autophagy also involve renal podocytes, mesangial cells, endothelial cells, and tubular epithelial cells that may compromise end-organ resistance in LN. Activation of mTOR complexes 1 (mTORC1) and 2 (mTORC2) has been identified as biomarkers of disease activation and predictors of disease flares and prognosis in SLE patients with and without LN. This review highlights recent advances in molecular pathogenesis of LN with a focus on immuno-metabolic checkpoints of autophagy and their roles in pathogenesis, prognosis and selection of targets for treatment in SLE.

Project description:Kidney stone disease is a lifestyle-related disease prevalent in developed countries; however, effective medical treatment for the disease is not yet well established. As cellular damage in renal tubular cells (RTCs) is responsible for the disease, here, we focused on the role of macroautophagy/autophagy in RTCs. We found that autophagic activity was significantly decreased in mouse RTCs exposed to calcium oxalate (CaOx) monohydrate crystals and in the kidneys of GFP-conjugated MAP1LC3B (microtubule- associated protein 1 light chain 3 beta) transgenic mice with CaOx nephrocalcinosis induced by glyoxylate. This caused accumulation of damaged intracellular organelles, such as mitochondria and lysosomes, the normal functioning of which is mediated by functional autophagy. An impairment of autophagy was also observed in the mucosa with plaques of CaOx kidney stone formers. We determined that the decrease in autophagy was caused by an upregulation of MTOR (mechanistic target of rapamycin kinase), which consequently resulted in the suppression of the upstream autophagy regulator TFEB (transcription factor EB). Furthermore, we showed that an MTOR inhibitor could recover a decrease in autophagy and alleviate crystal-cell interactions and the formation of crystals associated with increased inflammatory responses. Taken together, we conclude that autophagy compromised by MTOR deregulation is a fundamental feature in the pathology of kidney stone formation, and propose that chemical inhibition of MTOR could be a prospective strategy for disease suppression.Abbreviations: ACTB: actin, beta; CaOx: calcium oxalate; CKD: chronic kidney disease; COM: calcium oxalate monohydrate; LGALS3/galectin-3: lectin, galactose binding, soluble 3; GFP: green fluorescent protein; GOX: glyoxylate; HE: hematoxylin and eosin; MAPLC3B: microtubule- associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; ROS: reactive oxygen species; RTC: renal tubular cell; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TEM: transmission electron microscopy; tfLC3: tandem fluorescent-tagged LC3; 3-MA: 3-methyladenine.

Project description:BackgroundIntrauterine growth retardation (IUGR) affects approximately 10% to 15% of all pregnancies worldwide. IUGR is not only associated with stillbirth and newborn death, but also the delay of cognition in childhood and the promotion of metabolic and vascular disorders in adulthood. Figuring out the mechanism of IUGR is rather meaningful and valuable.MethodsDatasets related to IUGR were searched in the Gene Expression Omnibus website. Principal component analysis (PCA) was used for normalization. Differential expressed genes (DEGs) were screened out using the ggpot2 tool. DEGs were used to conduct Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses, and protein-protein interaction (PPI) analysis. IUGR related genes were searched in the OMIM website to look for the intersection with the DEGs. The DEGs were analyzed for tissue-specific expression by the online resource BioGPS. The results were displayed through volcano map, Venn map, box plot, heat map, and GSEA enrichment plots drawn by R language packages.ResultsEleven DEGs were screened out of 2 datasets. One hundred ninety-five genes related to IUGR in OMIM were retrieved. EGR2 was the only intersection gene that was found in both groups. Genes associated with placental tissue expression include COL17A1, HSD11B1, and LGALS14. Molecular functions of the DEGs are related to the oxidoreductase activity. The following 4 signaling pathways, reactome signaling by interleukins, reactome collagen degradation, Naba secreted factors, and PID NFAT tfpathway, were enriched by GSEA. Two critical modules comprising 5 up-regulated genes (LEP, PRL, TAC3, MMP14, and ADAMTS4) and 4 down-regulated genes (TIMP4, FOS, CCK, and KISS1) were identified by PPI analysis. Finally, we identified 6 genes (PRL, LGALS14, EGR2, TAC3, LEP, and KISS1) that are potentially relevant to the pathophysiology of IUGR.ConclusionThe candidate down-regulated genes LGALS14 and KISS1, as well as the up-regulated genes PRL, EGR2, TAC3, and LEP, were found to be closely related to IUGR by bioinformatics analysis. These hub genes are related to hypoxia and oxidoreductase activities in placental development. We provide useful and novel information to explore the potential mechanism of IUGR and make efforts to the prevention of IUGR.

Dataset Information

Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway.

Publications

Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway.

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