title: Akt Activation and Inhibition of Cytochrome C Release: Mechanistic Insights into Leptin-promoted Survival of Type II Alveolar Epithelial Cells.
abstract: Fetal growth restriction (FGR) increases the risk of perinatal death, partly due to defects in lung development. Leptin, a polypeptide hormone, is involved in fetal lung development. We previously demonstrated that treatment with exogenous leptin during gestation significantly promotes fetal lung maturity in the rat model of FGR. In this study, to delineate the molecular pathways through which leptin may enhance fetal lung development, we investigated the impact of leptin treatment on the survival of type II alveolar epithelial cells (AECs), essential leptin-responsive cells involved in lung development, in a rat model of FGR. The rat model of FGR was induced in pregnant Sprague-Dawley rats by partial uterine artery and vein ligation. In vivo and in vitro analyses of fetal lung tissues and freshly-isolated cultured AECs, respectively, showed that leptin protects type II AECs from hypoxia-induced apoptosis. Further molecular studies revealed the role of Akt activation in the leptin-mediated promotion of survival of type II AECs. The data also showed that the anti-apoptotic effects of leptin are dependent on phosphoinositol 3-kinase (PI3K) activation, and involve the down-regulation of caspases 3 and 9, upregulation of pro-survival proteins Bcl-2, and p-Bad, and inhibition of the release of cytochrome c from mitochondria. Taken together, our data suggested that leptin enhances the maturity of fetal lungs by mediating the regulation of caspase-3 and -9 during hypoxia-induced apoptosis of type II AECs and provide support for the potential of leptin as a therapeutic agent for promoting lung development in FGR.
authors.affiliation: Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Guangdong Province, China.|Key Laboratory of malignant tumor gene regulation and target therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Guangdong Province, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong Province, China.|Center for Disease Model Animals, Sun Yat-sen University, Guangdong Province, China.
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Liang
authors.affiliation: Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Guangdong Province, China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Guangdong Province, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Province, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangdong Province, China.
authors.forename: Xiang-Bin
authors.initials: XB
authors.lastname: Xing
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong Province, China.|Center for Disease Model Animals, Sun Yat-sen University, Guangdong Province, China.
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D047109:Fetal Development; D018507:Gene Expression Regulation, Developmental; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000254:growth & development / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000254:growth & development / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494821:Bad protein, rat; D020738:Leptin; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt
keywords: AKT; FETAL GROWTH RESTRICTION; LEPTIN; LUNG DEVELOPMENT