scholarly journals Sp1-Induced lncRNA Rmrp Promotes Mesangial Cell Proliferation and Fibrosis in Diabetic Nephropathy by Modulating the miR-1a-3p/JunD Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Hansen Yang ◽  
Jia Wang ◽  
Zheng Zhang ◽  
Rui Peng ◽  
Dan Lv ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Regulatory Mechanisms ◽  
Glomerular Mesangial Cells ◽  
Nuclear Transcription Factor ◽  
Mechanism Research ◽  
Mesangial Cell Proliferation ◽  
Non Coding Rnas ◽  
Subcellular Level

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. Long non-coding RNAs (lncRNAs) are regulators in DN progression. However, the regulatory mechanisms of multiple lncRNAs in DN remain to be determined. Our aim was to investigate the function and molecular mechanism of lncRNA RNA component of mitochondrial RNAase P (Rmrp) in DN. Here, we observed that the expression of Rmrp was up-regulated in the kidney of db/db DN mice and high glucose induced glomerular mesangial cells (MC). More importantly, the abnormal transcription of Rmrp was induced by nuclear transcription factor Sp1, which promotes the proliferation and production of fibrotic markers in MC. Subsequently, we screened the miRNAs related to Rmrp and found that Rmrp and miR-1a-3p are co-localized at the subcellular level of MC, and Rmrp could directly binds to miR-1a-3p. Further mechanism research demonstrated that the elevated miR-1a-3p significantly attenuated the proliferation and fibrosis-promoting effects induced by up-regulation of Rmrp. At the same time, we also investigated that miR-1a-3p can directly bind to Jun D proto-oncogene (JunD), thereby regulating the protein level of JunD. Rmrp-induced proliferation and fibrogenesis were reversed by co-transfection with JunD siRNA. In summary, Sp1 induced lncRNA Rmrp could drive the expression of JunD via sponging miR-1a-3p in DN progression.

scholarly journals LncRNA SOX2OT alleviates mesangial cell proliferation and fibrosis in diabetic nephropathy via Akt/mTOR-mediated autophagy

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Ke Chen ◽  
Bo Yu ◽  
Jie Liao
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Underlying Mechanism ◽  
Mesangial Cell Proliferation ◽  
Non Coding Rnas ◽  
Novel Target

Abstract Background Accumulating evidences have demonstrated that long non-coding RNAs (lncRNAs) are involved in the pathophysiology of diabetic nephropathy (DN). lncRNA SOX2OT plays an essential role in many diseases, including diabetes. Herein, we aim to investigate the underlying mechanism of lncRNA SOX2OT in DN pathogenesis. Methods Streptozotocin-induced DN mouse models and high glucose-induced mouse mesangial cells were constructed to examine the expression pattern of lncRNA SOX2OT. The activation of autophagy was evaluated using immunohistochemistry, immunofluorescence and western blot analysis, respectively. SOX2OT overexpressing plasmid was applied to further verify the functional role of SOX2OT in DN pathogenesis. CCK-8 and EDU assays were performed to the proliferation of mesangial cells. Additionally, rapamycin, the inhibitor of mTOR signaling, was used to further clarify whether SOX2OT controls DN development through Akt/mTOR pathway. Results lncRNA SOX2OT was markedly down-regulated both in streptozotocin-induced DN mice and high glucose-induced mouse mesangial cells. Moreover, overexpression of lncRNA SOX2OT was able to diminish the suppression of autophagy and alleviate DN-induced renal injury. Functionally, CCK-8 and EDU assays indicated that lncRNA SOX2OT overexpression significantly suppressed the proliferation and fibrosis of mesangial cells. Additionally, an obvious inhibition of Akt/mTOR was also observed with lncRNA SOX2OT overexpression, which was then further verified in vivo. Conclusion In summary, we demonstrated that lncRNA SOX2OT alleviates the pathogenesis of DN via regulating Akt/mTOR-mediated autophagy, which may provide a novel target for DN therapy.

scholarly journals Sauchinone Protects Renal Mesangial Cell Dysfunction against Angiotensin II by Improving Renal Fibrosis and Inflammation

2020 ◽  
Vol 21 (19) ◽  
pp. 7003
Author(s):  
Jung Joo Yoon ◽  
Hyeon Kyoung Lee ◽  
Hye Yoom Kim ◽  
Byung Hyuk Han ◽  
Ho Sub Lee ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Diabetic Nephropathy ◽  
Angiotensin Ii ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Biologically Active ◽  
Dependent Manner ◽  
Saururus Chinensis ◽  
Mesangial Cell Proliferation

Abnormal and excessive growth of mesangial cells is important in the pathophysiologic processes of diabetes-associated interstitial fibrosis and glomerulosclerosis, leading to diabetic nephropathy, which eventually turns into end-stage renal disease. Sauchinone, a biologically-active lignan isolated from aerial parts of Saururus chinensis, has anti-inflammatory and anti-viral activities effects on various cell types. However, there are no studies reporting the effects of sauchinone on diabetic nephropathy. The present study aims to investigate the role of sauchinone in mesangial cell proliferation and fibrosis induced by angiotensin II, as well as the underlying mechanisms of these processes. Human renal mesangial cells were induced by angiotensin II (AngII, 10 μM) in the presence or absence of sauchinone (0.1–1 μM) and incubated for 48 h. In this study, we found that AngII induced mesangial cell proliferation, while treatment with sauchinone inhibited the cell proliferation in a dose-dependent manner. Pre-treatment with sauchinone induced down-regulation of cyclins/CDKs and up-regulation of CDK inhibitor, p21, and p27kip1 expression. In addition, AngII-enhanced expression of fibrosis biomarkers such as fibronectin, collagen IV, and connective tissue growth factor (CTGF), which was markedly attenuated by sauchinone. Sauchinone also decreased AngII-induced TGF-β1 and Smad-2, Smad-3, and Smad-4 expression. This study further revealed that sauchinone ameliorated AngII-induced mesangial inflammation through disturbing activation of inflammatory factors, and NLRP3 inflammasome, which is composed of the NLRP3 protein, procaspase-1, and apoptosis-associated speck-like protein containing a CARD (ASC). Moreover, pretreatment of sauchinone inhibited NF-κB translocation and ROS production in AngII-exposed mesangial cells. These data suggest that sauchinone has a protective effect on renal proliferation, fibrosis and inflammation. Therefore, sauchinone might be a potential pharmacological agent in prevention of AngII-induced renal damage leading to diabetic nephropathy.

Knock-Down of Long Non-Coding RNA ANRIL Suppresses Mouse Mesangial Cell Proliferation, Fibrosis, Inflammation via Regulating Wnt/β-Catenin and MEK/ERK Pathways in Diabetic Nephropathy

2020 ◽  
Author(s):  
Xun Fang ◽  
Jun Hu ◽  
Hongyan Zhou
Keyword(s):  
Cell Proliferation ◽  
Diabetic Nephropathy ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Knock Down ◽  
Non Coding Rna ◽  
Mesangial Cell Proliferation ◽  
Long Non Coding Rna

Abstract Aims Our study aimed to investigate the role of long non-coding RNA ANRIL (lnc-ANRIL) knock-down in regulating cell activities, inflammation and downstream signaling pathways in mouse mesangial cellular diabetic nephropathy (DN) model. Methods The mouse mesangial cells (SV40-MES13 cells) were treated with high-glucose (HG) to construct cellular DN model. Lnc-ANRIL knock-down plasmid and control knock-down plasmid were transfected into HG-treated SV40-MES13 cells as Sh-ANRIL group and Sh-NC group respectively. Results Lnc-ANRIL expression was significantly higher in HG-treated SV40-MES13 cells compared with normal glucose-treated SV40-MES13 cells and osmotic control-treated SV40-MES13 cells. Lnc-ANRIL knock-down suppressed cell proliferation and promoted cell apoptosis in HG-treated SV40-MES13 cells. As for fibrosis, lnc-ANRIL knock-down reduced fibronectin and collagen I expressions in HG-treated SV40-MES13 cells. Besides, the expressions of supernatant tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β, IL-6, IL-8 and IL-18 were reduced in Sh-ANRIL group compared with Sh-NC group. Furthermore, Wnt3, β-catenin, p-MEK1 and p-ERK1 expressions were suppressed in Sh-ANRIL group compared with Sh-NC group, which suggested that lnc-ANRIL knock-down inhibited Wnt/β-catenin and MEK/ERK pathways in HG-treated SV40-MES13 cells. Conclusions Lnc-ANRIL knock-down suppresses mouse mesangial cell proliferation, fibrosis, inflammation, Wnt/β-catenin and MEK/ERK pathways in DN.

scholarly journals Rosiglitazone Inhibits Angiotensin II-Induced Proliferation of Glomerular Mesangial Cells via the Gαq/Plcβ4/TRPC Signaling Pathway

2017 ◽  
Vol 44 (6) ◽  
pp. 2228-2242 ◽  
Author(s):  
Linting Wei ◽  
Jiarong Mao ◽  
Jiamei Lu ◽  
Jie Gao ◽  
Dan Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Expression Levels ◽  
Qrt Pcr ◽  
Ppar Γ ◽  
Mesangial Cell Proliferation

Background/Aims: Mesangial cell proliferation and extracellular matrix accumulation (ECM) deposition play an important role in the pathogenesis of glomerulosclerosis. TRPC and PPAR-γ can regulate cell proliferation. Angiotensin II (AngII) can induce mesangial cell proliferation and affect TRPC expression. However, the mechanism has not been fully elucidated. This study was designed to investigate the role of TRPC and the effect of rosiglitazone (RSG) in the proliferation of rat glomerular mesangial cells (HBZY-1) that were stimulated by AngII and the underlying mechanisms. Methods: Immunofluorescence staining and qRT-PCR were performed to examine the expression levels of TRPCs in HBZY-1. Gene expression levels of TRPC, PPAR-γ, RGS4 (regulators of G protein signaling), the GPCR/Gαq/PLCβ4/TRPC signaling pathway and major downstream molecules (PCNA, SKP2, P21 and P27) were detected by qRT-PCR and western blotting. Additionally, changes in intracellular Ca2+ levels were determined through Fluo-4 Ca2+ imaging, and the cell cycle was analyzed by flow cytometry. Results: Our results found that TRPC1 and 6 were at higher expression levels in HBZY-1 cells. Following AngII stimulation, there were increased levels of TRPC1 and 6, Ca2+ entry, PCNA and SKP2, decreased expression levels of P21 and P27 and a reduced G0/G1 percentage. Silencing TRPC1 and 6 by siRNAs led to decrease in Ca2+ influx, G0/G1 cell cycle arrest and cell proliferation. Notably, PPAR-γ activation by RSG upregulated RGS4 expression, which can interact with the Gαq family to inhibit the Gαq-mediated signaling cascade. The results were similar to silencing TRPC1 and 6 by siRNAs. Conclusion: All these results indicate that RSG could inhibit HBZY-1 cell proliferation via the Gαq/PLCβ4/TRPC signaling pathway.

scholarly journals Heparin decreases mesangial matrix accumulation after selective antibody-induced mesangial cell injury.

1992 ◽  
Vol 3 (4) ◽  
pp. 921-929
Author(s):  
W W Tang ◽  
C B Wilson
Keyword(s):  
Cell Proliferation ◽  
Cell Injury ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Chronic Administration ◽  
Glomerular Mesangial Cells ◽  
Mesangial Matrix ◽  
Beneficial Effects ◽  
Mesangial Cell Proliferation ◽  
Matrix Accumulation

Anti-rat thymocyte antibody-induced injury of glomerular mesangial cells is characterized initially by lysis (1 h) and is followed by proliferation (beginning at 3 to 4 days), with resolution that can include a focal increase in mesangial matrix (by 28 days). Chronic administration (every 12 h) of heparin (anticoagulant or nonanticoagulant) resulted in a decrease in antibody-induced mesangial cell proliferation, which, in turn, was associated with a decrease in the size and number of areas of focal mesangial matrix increase. The effect could not be attributed to the effect of heparin on complement, to alterations in the small numbers of la-positive cells that characterize the lesion, or to binding of antibody to glomeruli. The beneficial effects of heparin in reducing mesangial cell proliferation, with a subsequent reduction in matrix increase, suggest that mesangial cell responses are a major element in the development of at least some forms of glomerulosclerosis. The possible mechanisms by which these effects of heparin may be achieved are discussed.

scholarly journals Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis

2003 ◽  
Vol 284 (6) ◽  
pp. F1171-F1180 ◽  
Author(s):  
Kazuhiko Bessho ◽  
Shinya Mizuno ◽  
Kunio Matsumoto ◽  
Toshikazu Nakamura
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Negative Regulator ◽  
Glomerular Mesangial Cells ◽  
Mesangial Cell Proliferation ◽  
Mesangioproliferative Glomerulonephritis

Activation and proliferation of glomerular mesangial cells play an important role in the development of mesangioproliferative glomerulonephritis. We investigated the role of hepatocyte growth factor (HGF) in regulating activated mesangial cell proliferation. In glomeruli of normal rats, mesangial cells barely expressed the c-Met/HGF receptor. However, when mesangioproliferative glomerulonephritis was induced in rats by the administration of an anti-Thy 1.1 antibody, glomerular HGF expression transiently decreased along with mesangiolysis, and activation of mesangial cells was associated with upregulation of the c-Met receptor. Activated mesangial cells in culture also expressed the c-Met/HGF receptor. Although addition of HGF to cultured mesangial cells did not increase DNA synthesis, HGF did diminish PDGF-induced DNA synthesis. PDGF induced activation of ERK, which continued for at least 48 h. When PDGF and HGF were simultaneously added, HGF inhibited the prolonged activation of ERK, which suggests that early inactivation of PDGF-induced ERK may be involved in the inhibitory effect of HGF on mesangial cell proliferation. Furthermore, administration of HGF to rats with anti-Thy 1.1 nephritis resulted in a selective suppression of activated mesangial cell proliferation, and this suppressive effect was associated with attenuation of phosphorylated glomerular ERK. These results indicate that HGF counteracts PDGF-induced mesangial cell proliferation and functions as a negative regulator of activated mesangial cell proliferation.

scholarly journals Ergosterol Ameliorates Diabetic Nephropathy by Attenuating Mesangial Cell Proliferation and Extracellular Matrix Deposition via the TGF-β1/Smad2 Signaling Pathway

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 483 ◽  
Author(s):  
Zhonghua Dong ◽  
Yueyue Sun ◽  
Guangwei Wei ◽  
Siying Li ◽  
Zhongxi Zhao
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Diabetic Mice ◽  
Mesangial Cell Proliferation ◽  
Tgf Β1

(1) Background: Diabetic nephropathy, a microvascular complication of diabetes, is one of the principal causes of end-stage renal disease worldwide. The aim of this study was to explore the therapeutic effects of ergosterol on diabetic nephropathy. (2) Methods: Streptozotocin (STZ)-induced C57BL/6 diabetic mice were treated with ergosterol (10, 20, 40 mg/kg/day) for 8 weeks by oral gavage. The in vitro study employed rat mesangial cells exposed to 30 mM glucose for 48 h in the presence of 10 or 20 μM ergosterol. (3) Results: Ergosterol treatment improved body weights, ameliorated the majority of biochemical and renal functional parameters and histopathological changes, and reduced extracellular matrix (ECM) deposition in diabetic mice. In vitro, ergosterol suppressed proliferation, reduced the levels of ECM proteins, and increased the expression of matrix metalloproteinase-2 and -9 in high glucose-induced mesangial cells; Furthermore, ergosterol markedly improved transforming growth factor-β1 (TGF-β1) expression, enhanced phosphorylation levels of drosophila mothers against decapentaplegic 2 (Smad2), and regulated the downstream factors in vivo and in vitro. (4) Conclusions: Ergosterol alleviated mesangial cell proliferation and the subsequent ECM deposition by regulating the TGF-β1/Smad2 signaling pathway.

Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy

2009 ◽  
Vol 297 (5) ◽  
pp. F1229-F1237 ◽  
Author(s):  
Danqing Min ◽  
J. Guy Lyons ◽  
James Bonner ◽  
Stephen M. Twigg ◽  
Dennis K. Yue ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Conditioned Medium ◽  
High Glucose ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Cell Conditioned Medium

Infiltration of macrophages to the kidney is a feature of early diabetic nephropathy. For this to happen monocytes must become activated, migrate from the circulation, and infiltrate the mesangium. This process involves degradation of extracellular matrix, a process mediated by matrix metalloproteinases (MMPs). In the present study we investigate the expression of proinflammatory cytokines TNF-α, IL-6, and MMP-9 in glomeruli of control and diabetic rodents and use an in vitro coculture system to examine whether factors secreted by mesangial cells in response to a diabetic milieu can induce monocyte MMP-9 expression and infiltration. After 8 wk of diabetes, the glomerular level of TNF-α, IL-6, and macrophage number and colocalization of MMP-9 with macrophage were increased ( P < 0.01). Coculture of THP1 monocytes and glomerular mesangial cells in 5 or 25 mM glucose increased MMP-9 (5 mM: 65% and 25 mM: 112%; P < 0.05) and conditioned media degradative activity (5 mM: 30.0% and 25 mM: 33.5%: P < 0.05). These effects were reproduced by addition of mesangial cell conditioned medium to THP1 cells. High glucose (25 mM) increased TNF-α, IL-6, and monocyte chemoattractant protein-1 in mesangial cell conditioned medium. These cytokines all increased adhesion and differentiation of THP1 cells ( P < 0.05), but only TNF-α and IL-6 increased MMP-9 expression (50- and 60-fold, respectively; P < 0.05). Our results show that mesangial cell-secreted factors increase monocyte adhesion, differentiation, MMP expression, and degradative capacity. High glucose could augment these effects by increasing mesangial cell proinflammatory cytokine secretion. This mesangial cell-monocyte interaction may be important in activating monocytes to migrate from the circulation to the kidney in the early stages of diabetic nephropathy.

scholarly journals Tumor necrosis factor alpha activates soluble guanylate cyclase in bovine glomerular mesangial cells via an L-arginine-dependent mechanism.

1990 ◽  
Vol 172 (6) ◽  
pp. 1843-1852 ◽  
Author(s):  
P A Marsden ◽  
B J Ballermann
Keyword(s):  
Guanylate Cyclase ◽  
Mesangial Cell ◽  
Soluble Guanylate Cyclase ◽  
Mesangial Cells ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Concentration Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Factor Alpha

Endothelium-derived nitric oxide (NO) causes vasodilatation by activating soluble guanylate cyclase, and glomerular mesangial cells respond to NO with elevations of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). We explored whether mesangial cells can be stimulated to produce NO and whether NO modulates mesangial cell function in an autocrine or paracrine fashion. Tumor necrosis factor alpha (TNF-alpha) raised mesangial cell cGMP levels in a time- and concentration-dependent manner (threshold dose 1 ng/ml, IC50 13.8 ng/ml, maximal response 100 ng/ml). TNF-alpha-induced increases in mesangial cGMP content were evident at 8 h and maximal at 18-24 h. The TNF-alpha-induced stimulation of mesangial cell cGMP production was abrogated by actinomycin D or cycloheximide suggesting dependence on new RNA or protein synthesis. Hemoglobin and methylene blue, both known to inhibit NO action, dramatically reduced TNF-alpha-induced mesangial cell cGMP production. Superoxide dismutase, known to potentiate NO action, augmented the TNF-alpha-induced effect. Ng-monomethyl-L-arginine (L-NMMA) decreased cGMP levels in TNF-alpha-treated, but not vehicle-treated mesangial cells in a concentration-dependent manner (IC50 53 microM). L-arginine had no effect on cGMP levels in control or TNF-alpha-treated mesangial cells but reversed L-NMMA-induced inhibition. Interleukin 1 beta and lipopolysaccharide (LPS), but not interferon gamma, also increased mesangial cell cGMP content. Transforming growth factor beta 1 blunted the mesangial cell response to TNF-alpha. TNF-alpha-induced L-arginine-dependent increases in cGMP were also evident in bovine renal artery vascular smooth muscle cells, COS-1 cells, and 1502 human fibroblasts. These findings suggest that TNF-alpha induces expression in mesangial cell of an enzyme(s) involved in the formation of L-arginine-derived NO. Moreover, the data indicate that NO acts in an autocrine and paracrine fashion to activate mesangial cell soluble guanylate cyclase. Cytokine-induced formation of NO in mesangial and vascular smooth muscle cells may be implicated in the pathogenesis of septic shock.

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