Rapamycin at subimmunosuppressive levels inhibits mesangial cell proliferation and extracellular matrix production

2007 ◽  
Vol 292 (1) ◽  
pp. F76-F81 ◽  
Author(s):  
Helen R. Lock ◽  
Steven H. Sacks ◽  
Michael G. Robson
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Mechanism Of Action ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Primary Cultures ◽  
Cell Number ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Mesangial Cell Proliferation

In view of its proven antiproliferative effects, rapamycin offers potential in the treatment of mesangioproliferative disease. Previous data have shown an effect of rapamycin on mesangial cell proliferation at high doses and have not explored the mechanism of action. Therefore, we explored the effects and mechanism of action of low levels of rapamycin on mesangial cell proliferation. Primary cultures of mouse mesangial cells were grown in medium containing serum with differing concentrations of rapamycin. A rapamycin concentration of 0.1 ng/ml caused a decrease in cell number and DNA synthesis with no effect on apoptosis. Type IV collagen protein production was inhibited at 0.01 ng/ml rapamycin, although gene expression was unaffected. P70S6K phosphorylation was inhibited in parallel with the effects on cell number and DNA synthesis in a dose-dependent manner, but no effect was seen at 0.01 ng/ml rapamycin. These data show an effect on mesangial cell proliferation and p70S6 kinase phosphorylation of 0.1 ng/ml rapamycin and an effect on collagen IV production of 0.01 ng/ml rapamycin. We suggest that further in vivo studies should explore the potential for low-dose rapamycin in the treatment of mesangioproliferative glomerulonephritis.

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.

scholarly journals A positive feedback loop involving Erk5 and Akt turns on mesangial cell proliferation in response to PDGF

2014 ◽  
Vol 306 (11) ◽  
pp. C1089-C1100 ◽  
Author(s):  
Amit Bera ◽  
Falguni Das ◽  
Nandini Ghosh-Choudhury ◽  
Xiaonan Li ◽  
Sanjay Pal ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Positive Feedback ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Mesangial Cell Proliferation

Platelet-derived growth factor BB and its receptor (PDGFRβ) play a pivotal role in the development of renal glomerular mesangial cells. Their roles in increased mesangial cell proliferation during mesangioproliferative glomerulonephritis have long been noted, but the operating logic of signaling mechanisms regulating these changes remains poorly understood. We examined the role of a recently identified MAPK, Erk5, in this process. PDGF increased the activating phosphorylation of Erk5 and tyrosine phosphorylation of proteins in a time-dependent manner. A pharmacologic inhibitor of Erk5, XMD8-92, abrogated PDGF-induced DNA synthesis and mesangial cell proliferation. Similarly, expression of dominant negative Erk5 or siRNAs against Erk5 blocked PDGF-stimulated DNA synthesis and proliferation. Inhibition of Erk5 attenuated expression of cyclin D1 mRNA and protein, resulting in suppression of CDK4-mediated phosphorylation of the tumor suppressor protein pRb. Expression of cyclin D1 or CDK4 prevented the dominant negative Erk5- or siErk5-mediated inhibition of DNA synthesis and mesangial cell proliferation induced by PDGF. We have previously shown that phosphatidylinositol 3-kinase (PI3-kinase) contributes to PDGF-induced proliferation of mesangial cells. Inhibition of PI3-kinase blocked PDGF-induced phosphorylation of Erk5. Since PI3-kinase acts through Akt, we determined the role of Erk5 on Akt phosphorylation. XMD8-92, dominant negative Erk5, and siErk5 inhibited phosphorylation of Akt by PDGF. Interestingly, we found inhibition of PDGF-induced Erk5 phosphorylation by a pharmacological inhibitor of Akt kinase and kinase dead Akt in mesangial cells. Thus our data unfold the presence of a positive feedback microcircuit between Erk5 and Akt downstream of PI3-kinase nodal point for PDGF-induced mesangial cell proliferation.

Poria cocosInhibits High Glucose-Induced Proliferation of Rat Mesangial Cells

2013 ◽  
Vol 41 (01) ◽  
pp. 71-83 ◽  
Author(s):  
Jung Joo Yoon ◽  
Yun Jung Lee ◽  
So Min Lee ◽  
Song Nan Jin ◽  
Dae Gill Kang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
High Glucose ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Water Extract ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Proliferative Effect ◽  
Mesangial Cell Proliferation ◽  
Mitogen Activated Protein

Mesangial cell proliferation is correlated with the progression of renal failure. The purpose of this study was to determine whether a water extract of Poria cocos Wolf (WPC), a well-known medicinal plant, regulates rat mesangial cell proliferation in the presence of high glucose (HG). HG significantly accelerated [3H]-thymidine incorporation, which was inhibited by WPC (1–50 μg/mL) in a dose-dependent manner. Cell migration and fibronectin mRNA expression data also supported the anti-proliferative effect of WPC. Western blot analysis revealed that pretreatment with WPC decreased the expression of cyclins and cyclin-dependent kinases (CDKs) and promoted the expression of p21waf1/cip1and p27kip1. WPC also suppressed HG-induced p38 mitogen-activated protein kinase (p38 MAPK) and extracellular-signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Furthermore, WPC inhibited HG-induced production of dichlorofluorescein (DCF)-sensitive intracellular reactive oxygen species (ROS). In conclusion, HG promoted mesangial cell proliferation, and WPC inhibited this activity, at least in part, via induction of cell cycle arrest and activation of anti-oxidant properties. Taken together, these results suggest that P. cocos may be a potent regulator of HG-induced proliferation.

scholarly journals HDL causes mesangial cell mitogenesis through a tyrosine kinase-dependent receptor mechanism.

1997 ◽  
Vol 8 (8) ◽  
pp. 1247-1256
Author(s):  
N I Neverov ◽  
G A Kaysen ◽  
R Nuccitelli ◽  
R H Weiss
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Dna Synthesis ◽  
Mesangial Cell ◽  
Thymidine Incorporation ◽  
Mesangial Cells ◽  
Mitogenic Effect ◽  
Kinase C ◽  
Mesangial Cell Proliferation

Hypercholesterolemia and mesangial cell proliferation have been proposed to play a role in the progression of glomerulosclerosis in diabetic nephropathy and other renal diseases. Although LDL is mitogenic for and cytotoxic to mesangial cells, the effect of HDL on these cells is unknown. HDL stimulates fibroblast mitogenesis and is the principal cholesterol-bearing lipoprotein in the rat, the experimental model for studying the effect of hyperlipidemia on renal disease. Insulin is mitogenic in several cell systems, and its levels are increased in serum in non-insulin-dependent diabetes mellitus. This study investigates whether HDL acts as a growth factor in mesangial cells and whether it functions in parallel with insulin. It was found that HDL at protein concentrations between 10 and 500 microg/ml, both alone and in the presence of 100 nM insulin, increased DNA synthesis in mesangial cells (129 to 165% of control for HDL alone; 140 to 235% for HDL plus insulin), whereas HDL at 1000 microg/ml and greater inhibited mesangial cell proliferation. Insulin alone at 100 nM stimulated [3H]thymidine incorporation in the same cell system (145% of control); the mitogenic effect of insulin was additive to that of HDL. Purified apo A-I had a similar effect, but at significantly lower concentrations. Specific binding of HDL to mesangial cells was demonstrated (B(max) [binding constant] of 5.19 +/- 0.70 x 10(-7) micromol of HDL bound/mg cell protein and K(b) of 2.83 +/- 0.22 nM). Tetranitromethane alters apo A-I, preventing binding to its cognate receptor. Tetranitromethane-modified HDL did not bind to mesangial cells and had no effect on [3H]thymidine incorporation. Addition of HDL to mesangial cells caused an immediate transient increase in free intracellular calcium in several representative mesangial cells, similar to the response seen with platelet-derived growth factor. The mitogenic effect of HDL was not altered after attenuation of cellular protein kinase C activity, but the stimulatory effect of HDL alone and in combination with insulin on DNA synthesis was completely eliminated after inhibition of cellular tyrosine kinases by 24-h pretreatment with 0.25 microM herbimycin A. Thus, HDL binds to a specific apo A-I-dependent receptor, promotes DNA synthesis, and initiates second-messenger events by a tyrosine kinase-dependent and protein kinase C-independent mechanism.

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 Expression of Megsin mRNA, a Novel Mesangium-Predominant Gene, in the Renal Tissues of Various Glomerular Diseases

1999 ◽  
Vol 10 (12) ◽  
pp. 2606-2613
Author(s):  
DAISUKE SUZUKI ◽  
TOSHIO MIYATA ◽  
MASAOMI NANGAKU ◽  
HIDEO TAKANO ◽  
NOBORU SAOTOME ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Periodic Acid ◽  
Cell Number ◽  
Mesangial Matrix ◽  
Periodic Acid Schiff ◽  
Glomerular Diseases ◽  
Mesangial Cell Proliferation ◽  
Matrix Expansion

Abstract. Mesangial cells play an important role in maintaining a structure and function of the glomerulus and in the pathogenesis of glomerular diseases. Recently, we discovered a new mesangium-predominant gene termed “megsin.” Megsin is a novel protein that belongs to the serine protease inhibitor (serpin) superfamily. To elucidate the pathophysiologic role of megsin in the kidney, the expression and localization of megsin mRNA in renal tissues of patients with IgA nephropathy (IgA-N), diabetic nephropathy (DN), minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN), and normal human kidney (NHK) was evaluated by in situ hybridization using digoxigenin-labeled oligonucleotide. Individual cells positive for megsin mRNA were observed only in glomeruli in all renal tissues. Their localization coincided with those of mesangial cells. The percentage of positive cells for megsin mRNA in total glomerular cells was significantly greater in IgA-N than in MCNS, MN, and NHK. It was also significantly greater in DN than in MCNS and NHK. In IgA-N, the percentage of megsin mRNA-positive cells was greater in tissues from those with mesangial cell proliferation and slightly mesangial matrix expansion (periodic acid-Schiff-positive area in the total glomerulus area, <30%; cell number in mesangial matrix area, >30; assessed in cross-sections through their vascular poles) than in tissues from those with severe mesangial matrix expansion (periodic acid-Schiff-positive area in total glomerulus area, >30%; cell number in mesangial matrix area, <30). In conclusion, megsin mRNA was predominantly expressed in glomerular mesangial cells in all renal tissues. The expression of megsin mRNA was upregulated in IgA-N and DN, both of which are diseases accompanied with mesangial cell proliferation and/or mesangial matrix expansion. These data suggest a link of megsin expression to the pathogenesis of IgA-N and DN, two major causes of end-stage renal failure.

scholarly journals Smooth-Muscle Calponin in Mesangial Cells: Regulation of Expression and a Role in Suppressing Glomerulonephritis

2002 ◽  
Vol 13 (2) ◽  
pp. 322-331 ◽  
Author(s):  
Youichi Sugenoya ◽  
Ashio Yoshimura ◽  
Hisako Yamamura ◽  
Kiyoko Inui ◽  
Hiroyuki Morita ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Actin Binding ◽  
Luciferase Reporter ◽  
Tnf Α ◽  
Mesangial Cell Proliferation ◽  
Tgf Β1

ABSTRACT. The basic or h1 calponin gene, which encodes an actin-binding protein involved in the regulation of smooth-muscle shortening velocity, is known to be a smooth-muscle differentiation-specific gene. It was found that basic calponin was expressed by cultured mesangial cells and localized along the actin filaments. Among the growth factors involved in the mesangial cell pathophysiology, including platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor–α (TNF-α), and transforming growth factor–β1 (TGF-β1), TNF-α potently downregulates basic calponin expression in both the mRNA and protein levels, whereas TGF-β1 upregulates the calponin expression. PDGF-BB also reduced its mRNA expression. The half-life of basic calponin mRNA was determined to be similar between TNF-α–treated and –untreated mesangial cells, whereas cell transfection assays that used a luciferase reporter gene construct containing the functional basic calponin promoter showed that TNF-α and PDGF-BB reduced the transcriptional activity. Because stimulation with TNF-α and PDGF-BB was associated with mesangial cell proliferation, basic calponin may play a role in the suppression of mesangial cell proliferation. Treatment with anti–glomerular basement membrane antibody in calponin knockout mice induced more severe nephritis than in wild type mice, as judged from an increase in the urinary protein excretion, glomerular cellularity, and number of proliferating cell nuclear antigen–positive cells in glomerulus. These results suggest that basic calponin expression may serve as one of the intrinsic regulators of glomerular nephritis. Elucidation of the molecular mechanisms for regulation of the basic calponin expression in mesangial cells may improve the understanding of the molecular basis and pathogenesis of the glomerular response to injury.

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.

Bimodal effects of platelet-derived growth factor on rat mesangial cell proliferation and death, and the role of lysophosphatidic acid in cell survival

2001 ◽  
Vol 101 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Chiyoko N. INOUE ◽  
Isao NAGANO ◽  
Ryo ICHINOHASAMA ◽  
Natsumi ASATO ◽  
Yoshiaki KONDO ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Growth Factor ◽  
Lysophosphatidic Acid ◽  
Culture Medium ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Platelet Derived Growth Factor ◽  
P53 Expression ◽  
Mesangial Cell Proliferation

Although mesangial cell death has been shown to be correlated with mesangial cell mitosis in vivo, little is known about how these two apparently opposite events are regulated. We show that the addition of platelet-derived growth factor (PDGF; 10–50 ng/ml) to primary cultured rat mesangial cells for 24 h caused continuous proliferation along with simultaneous cell death. This process was accompanied by the fragmentation of DNA into nucleosomal oligomers, the development of apoptotic morphological changes in the nucleus, and increased expression of p53. Accumulation of lactate dehydrogenase (LDH) was also observed in the culture medium, suggesting that both apoptosis and necrosis are involved in the cell death mechanisms observed. We also observed that addition of 30 µM lysophosphatidic acid (LPA) to the culture medium greatly suppressed PDGF-induced cell death, leading to synergistically enhanced mesangial cell proliferation. DNA fragmentation, p53 expression and LDH release were all suppressed by LPA. We suggest that PDGF is a bifunctional molecule in mesangial cells that evokes both cell proliferation and cell death simultaneously, whereas LPA is a survival factor. We speculate that PDGF and LPA may play important roles in the progression or exacerbation of proliferative glomerulonephritis.

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