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Repression of microRNA-382 inhibits glomerular mesangial cell proliferation and extracellular matrix accumulation via FoxO1 in mice with diabetic nephropathy.

ABSTRACT: OBJECTIVES:Diabetic nephropathy (DN) is a nerve damaging disorder, characterized by glomerular mesangial cell expansion and accumulation of extracellular matrix (ECM) proteins. In this study, we aimed to investigate mesangial cell proliferation and ECM accumulation when promoting or suppressing endogenous miR-382 in glomerular mesangial cells of DN. MATERIALS AND METHODS:Model establishment consisted of DN induction by streptozotocin (STZ) in mice. The underlying regulatory mechanisms of miR-382 were analysed in concert with the treatment of miR-382 mimics, miR-382 inhibitors or siRNA against FoxO1 in cultured glomerular mesangial cells isolated from DN mice. RESULTS:FoxO1 was identified as the downregulated gene in DN based on the microarray data of GSE1009. We found that miR-382 was significantly upregulated in renal tissues of DN mice and its downregulation dephosphorylated FoxO1, reduced glomerular mesangial cell proliferation and ECM accumulation in vitro. The determination of luciferase activity suggested that miR-382 negatively targeted FoxO1. Expectedly, distinct levels of phosphorylated FoxO1 were observed in the renal cortices of DN mice, while the silencing of FoxO1 was found to increase glomerular mesangial cell proliferation and ECM accumulation in vitro. Reduced glomerular mesangial cell proliferation and ECM accumulation elicited by miR-382 inhibitors were reversed by silencing FoxO1. CONCLUSIONS:This study demonstrates miR-382 suppression exerts a potent anti-proliferative effect that may be applied to inhibit glomerular mesangial cell proliferation and ECM accumulation in DN.

SUBMITTER: Wang S

PROVIDER: S-EPMC6528942 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Repression of microRNA-382 inhibits glomerular mesangial cell proliferation and extracellular matrix accumulation via FoxO1 in mice with diabetic nephropathy.

Wang Shan S Wen Xin X Han Xin-Rui XR Wang Yong-Jian YJ Shen Min M Fan Shao-Hua SH Zhuang Juan J Zhang Zi-Feng ZF Shan Qun Q Li Meng-Qiu MQ Hu Bin B Sun Chun-Hui CH Wu Dong-Mei DM Lu Jun J Zheng Yuan-Lin YL

Cell proliferation 20180427 5

<h4>Objectives</h4>Diabetic nephropathy (DN) is a nerve damaging disorder, characterized by glomerular mesangial cell expansion and accumulation of extracellular matrix (ECM) proteins. In this study, we aimed to investigate mesangial cell proliferation and ECM accumulation when promoting or suppressing endogenous miR-382 in glomerular mesangial cells of DN.<h4>Materials and methods</h4>Model establishment consisted of DN induction by streptozotocin (STZ) in mice. The underlying regulatory mechan ...[more]

PMID: 29701296

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Project description:The dysfunction of mesangial cells (MCs) in high-glucose (HG) conditions plays pivotal role in inducing glomerular sclerosis by causing the imbalance between generation and degradation of extracellular matrix (ECM) proteins, which ultimately leads to diabetic nephropathy. This study was designed to determine the function of forkhead box protein O1 (FoxO1), an important transcription factors in regulating cell metabolism and oxidative stress, in MCs in HG conditions. Up-regulation of fibronectin, collagen type IV, and plasminogen activator inhibitor (PAI-1) was observed under HG conditions in vivo and in vitro, accompanied with elevation of protein kinase B (Akt) phosphorylation and reduction of FoxO1 bioactivity. After overexpression of constitutively active (CA) FoxO1 in vivo and in vitro by using lentivirus vector, in vivo and in vitro, FoxO1 expression and activity was increased, in accordance with up-regulation of antioxidative genes (catalase and superoxide dismutase, leading to alleviated oxidative stress as well as attenuated Akt activity, whereas overexpression of wild type-FoxO1 only expressed partial effect. Moreover, CA-FoxO1 decreased the expression of fibronectin, collagen type IV, and PAI-1, causing amelioration of renal pathological changes and decrease of ECM protein deposition in glomerulus. Overexpression of CA-FoxO1 in renal cortex also decreased activin type-I receptor-like kinase-5 levels and increased signaling mothers against decapentaplegic (Smad) 7 levels, and simultaneously inhibited Smad3 phosphorylation. Results from in vitro study indicated that increased combination of FoxO1 and Smad3 may interfere with the function of Smad3, including Smad3 phosphorylation and translocation, interaction with cAMP response element binding protein (CREB)-binding protein, and binding with PAI-1 promoter. Together, our findings shed light on the novel function of FoxO1 in inhibiting ECM deposition, which is beneficial to ameliorate MC dysfunction.

Dataset Information

Repression of microRNA-382 inhibits glomerular mesangial cell proliferation and extracellular matrix accumulation via FoxO1 in mice with diabetic nephropathy.

Publications

Repression of microRNA-382 inhibits glomerular mesangial cell proliferation and extracellular matrix accumulation via FoxO1 in mice with diabetic nephropathy.

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