title: Lentiviral Vector-Mediated FoxO1 Overexpression Inhibits Extracellular Matrix Protein Secretion Under High Glucose Conditions in Mesangial Cells.
abstract: Diabetic nephropathy is characterized by inordinate secretion of extracellular matrix (ECM) proteins from mesangial cells (MCs), which is tightly associated with excessive activation of TGF-β signaling. The forkhead transcription factor O1 (FoxO1) protects mesangial cells from hyperglycemia-induced oxidative stress, which may be involved in ameliorating the redundant secretion of ECM proteins under high glucose conditions. Here, we reported that high glucose elevated the level of p-Akt to attenuate endogenous FoxO1 bioactivities in MCs, accompanied with decreases in the mRNA expressions of catalase (CAT) and superoxide dismutase 2 (SOD2). Meanwhile, the expressions of major ECM proteins-FN and Col I-increased under high glucose conditions, in consistent with the activation of TGF-β/Smad signaling. By contrast, overexpression of nucleus-localized FoxO1 (insensitive to Akt phosphorylation) directly up-regulated the expressions of anti-oxidative enzymes, accompanied with inactivation of TGF-β/Smad3 pathway, as well as decreases of extracellular matrix proteins. Moreover, similar to those MCs overexpressed of nucleus-localized FoxO1 in high glucose conditions, MCs with down-regulation of FoxO1 by small interference-RNA under normal glucose conditions showed increased FN level and activated TGF-β/Smad3 pathway. Our findings link the anti-oxidative activity of FoxO1 and the TGF-β-induced secretion of ECM proteins, indicating the novel role of FoxO1 in protecting MCs under high glucose conditions.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Yingni
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wu
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ma
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Fengjuan
authors.initials: F
authors.lastname: Huang
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Guijun
authors.initials: G
authors.lastname: Qin
mesh_terms: D000818:Animals; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats
chemical_list: D016326:Extracellular Matrix Proteins; D051858:Forkhead Transcription Factors; D005947:Glucose
keywords: EXTRACELLULAR MATRIX; FORKHEAD TRANSCRIPTION FACTOR O1; GLOMERULAR MESANGIAL CELL; LENTIVIRAL VECTORS; OXIDATIVE STRESS; TRANSFORMING GROWTH FACTOR-Β PATHWAY