Bradykinin induces tubulin phosphorylation and nuclear  translocation of MAP kinase in mesangial cells

Glomerular hypertension and glomerular hypertrophy act early and synergistically to promote glomerular injury in diabetes. We have previously shown that increased renal kinin production contributes to the glomerular hemodynamic abnormalities associated with diabetes. Glomerulosclerosis, characterized by mesangial cell proliferation and matrix expansion, is the final pathway leading to renal failure. The signal(s) initiating mesangial cell proliferation is ill defined. In the present study, we utilized immunofluorescence, immunoprecipitation, and immunoblotting techniques to identify substrates that are tyrosine phosphorylated in response to bradykinin action in mesangial cells. Immunofluorescence microscopy of mesangial cells stained with anti-phosphotyrosine (anti-PY) antibodies following bradykinin treatment (10−9–10−6M) revealed a dose-dependent increase in the labeling of cytoplasmic and nuclear proteins. Immunoprecipitation with anti-PY, followed by immunoblot revealed bradykinin-induced tyrosyl phosphorylation of tubulin and mitogen-activated protein kinase (MAPK). Confocal microscopy of mesangial cells stained for MAPK indicated that bradykinin stimulation resulted in translocation of MAPK from the cytoplasm to the nucleus by 2 h. These data demonstrate that bradykinin action results in the tyrosine phosphorylation of cellular proteins in mesangial cells and suggest a role for tubulin and MAPK in the signaling cascade of bradykinin leading to altered mesangial function.

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Poria cocosInhibits High Glucose-Induced Proliferation of Rat Mesangial Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x13500067 ◽

2013 ◽

Vol 41 (01) ◽

pp. 71-83 ◽

Cited By ~ 8

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.

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Atherogenic lipoproteins stimulate mesangial cell p42 mitogen-activated protein kinase.

Journal of the American Society of Nephrology ◽

10.1681/asn.v93488 ◽

1998 ◽

Vol 9 (3) ◽

pp. 488-496

Author(s):

B V Bassa ◽

D D Roh ◽

M A Kirschenbaum ◽

V S Kamanna

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Map Kinase ◽

Mesangial Cell ◽

Mesangial Cells ◽

Mitogen Activated Protein Kinase ◽

Time Points ◽

Mesangial Cell Proliferation ◽

Mitogen Activated Protein ◽

Oxidatively Modified

Previously, it has been shown that atherogenic lipoproteins, through the activation of glomerular cells, stimulate pathobiological processes involved in monocyte infiltration into the mesangium. This study examined the role of LDL and its oxidatively modified variants (mildly oxidatively modified LDL [mm-LDL] and oxidatively modified LDL [ox-LDL]) on the activation of mesangial cell p42 mitogen-activated protein kinase (MAP kinase), a key intracellular signaling mechanism associated with cell proliferation. The incubation of mesangial cells with either LDL, mm-LDL, or ox-LDL induced the activation of MAP kinase dose dependently. The activation of MAP kinase by these lipoproteins in mesangial cells occurred biphasically: initially at 15 min of incubation period and at later time points of 8 to 24 h. No activation of MAP kinase was noted between 30 min (except in LDL) and 6 h. The induction of MAP kinase by both mm-LDL and ox-LDL was greater by 1.5- to 2-fold when compared with LDL. Similarly, these atherogenic lipoproteins stimulated mesangial cell proliferation. Lysophosphatidylcholine, a component of both oxidatively modified variants of LDL, markedly stimulated mesangial cell MAP kinase activity at early incubation times (5 to 30 min) but not at later time points (3 to 24 h), suggesting that lysophosphatidylcholine may, at least in part but not solely, act as an active component of ox-LDL-mediated effects. These data define putative key signal transduction events associated with lipoprotein-mediated induction of mesangial cell proliferation.

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Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice

AJP Renal Physiology ◽

10.1152/ajprenal.90680.2008 ◽

2009 ◽

Vol 297 (3) ◽

pp. F679-F684 ◽

Cited By ~ 30

Author(s):

Mari Tomiyama-Hanayama ◽

Hiromi Rakugi ◽

Masaharu Kohara ◽

Toru Mima ◽

Yasuo Adachi ◽

...

Keyword(s):

Cell Proliferation ◽

Apolipoprotein E ◽

Interleukin 6 ◽

Renal Injury ◽

Mesangial Cell ◽

Organ Damage ◽

Glomerular Injury ◽

Mesangial Cell Proliferation ◽

Matrix Expansion ◽

Interleukin 6 Receptor

Hyperlipidemia has been demonstrated to be associated with renal disease, yet the mechanism of renal injury is still poorly understood. Inflammation that occurs with the hyperlipidemia has been considered to play an important role in development of glomerular injury. In the present study, we investigated the role of interleukin-6 (IL-6), a key inflammatory molecule, on renal injury in apolipoprotein E-deficient (ApoE−/−) mice with severe hypercholesterolemia. The 6-wk-old mice were fed a high-fat diet and administered weekly rat anti-IL-6 receptor monoclonal antibody (MR16-1), control rat IgG, or saline for a total of 4 wk. We examined histopathological changes in the kidney and urinary excretion of protein and albumin. Saline- and IgG-treated mice showed remarkable proteinuria at 10 wk of age, whereas MR16-1-treated mice exhibited significantly lower levels. Renal histopathology of saline- and IgG-treated mice revealed striking lipid deposits and foam cells in the glomerular tuft, juxtaglomerular area, and arteriolar wall along with range of mesangial cell proliferation and matrix expansion. Notably, the severity of lipid deposits and mesangial cell proliferation were significantly reduced in MR16-1-treated mice. Immunohistochemistry demonstrated that mesangial IL-6 expression was dramatically reduced in MR16-1-treated mice compared with IgG-treated mice. Blocking the IL-6 receptor prevented progression of proteinuria and renal lipid deposit, as well as the mesangial cell proliferation associated with severe hyperlipoproteinemia. These results clearly demonstrate that IL-6 plays an essential role in the pathogenesis of hyperlipidemia-induced glomerular injury in ApoE−/− mice and suggests the usefulness of anti-IL-6 receptor antibody in treatments for hyperlipidemia-induced organ damage.

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Interleukin 1 beta‐induced calcium signaling via TRPA1 channels promotes mitogen‐activated protein kinase‐dependent mesangial cell proliferation

The FASEB Journal ◽

10.1096/fj.202100367r ◽

2021 ◽

Vol 35 (7) ◽

Author(s):

Hitesh Soni ◽

Ravi Kumar ◽

Praghalathan Kanthakumar ◽

Adebowale Adebiyi

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Calcium Signaling ◽

Mesangial Cell ◽

Interleukin 1 ◽

Mitogen Activated Protein Kinase ◽

Interleukin 1 Beta ◽

Mesangial Cell Proliferation ◽

Mitogen Activated Protein

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Involvement of mineralocorticoid receptor in high glucose-induced big mitogen-activated protein kinase 1 activation and mesangial cell proliferation

Journal of Hypertension ◽

10.1097/hjh.0b013e3283346b62 ◽

2010 ◽

Vol 28 (3) ◽

pp. 536-542 ◽

Cited By ~ 9

Author(s):

Gang Liu ◽

Kayoko Miyata ◽

Hirofumi Hitomi ◽

Li Yao ◽

Guang-Ping Sun ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

High Glucose ◽

Mineralocorticoid Receptor ◽

Mesangial Cell ◽

Mitogen Activated Protein Kinase ◽

Mesangial Cell Proliferation ◽

Mitogen Activated Protein

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LPA is a novel lipid regulator of mesangial cell hexokinase activity and HKII isoform expression

AJP Renal Physiology ◽

10.1152/ajprenal.00093.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. F271-F279 ◽

Cited By ~ 5

Author(s):

Platina E. Coy ◽

Navin Taneja ◽

Iris Lee ◽

Claudie Hecquet ◽

Jane M. Bryson ◽

...

Keyword(s):

Protein Kinase ◽

Mesangial Cell ◽

Mesangial Cells ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Glomerular Injury ◽

Mitogen Activated Protein ◽

Extracellular Lipid ◽

Cell Mitogen

The prototypical extracellular phospholipid mediator, lysophosphatidic acid (LPA), exhibits growth factor-like properties and represents an important survival factor in serum. This potent mesangial cell mitogen is increased in conditions associated with glomerular injury. It is also a known activator of the classic mitogen-activated protein kinase (MAPK) pathway, which plays an important role in the regulation of mesangial cell hexokinase (HK) activity. To better understand the mechanisms coupling metabolism to injury, we examined the ability of LPA to regulate HK activity and expression in cultured murine mesangial cells. LPA increased total HK activity in a concentration- and time-dependent manner, with maximal increases of >50% observed within 12 h of exposure to LPA concentrations ≥25 μM (apparent ED50 2 μM). These effects were associated with increased extracellular signal-regulated kinase (ERK) activity and were prevented by the pharmacological inhibition of either MAPK/ERK kinase or protein kinase C (PKC). Increased HK activity was also associated with increased glucose (Glc) utilization and lactate accumulation, as well as selectively increased HKII isoform abundance. The ability of exogenous LPA to increase HK activity was both Ca2+independent and pertussis toxin insensitive and was mimicked by LPA-generating phospholipase A2. We conclude that LPA constitutes a novel lipid regulator of mesangial cell HK activity and Glc metabolism. This regulation requires sequential activation of both Ca2+-independent PKC and the classic MAPK pathway and culminates in increased HKII abundance. These previously unrecognized metabolic consequences of LPA stimulation have both physiological and pathophysiological implications. They also suggest a novel mechanism whereby metabolism may be coupled to cellular injury via extracellular lipid mediators.

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Deoxyspergualin inhibits mesangial cell proliferation and major histocompatibility complex class II expression.

Journal of the American Society of Nephrology ◽

10.1681/asn.v5111895 ◽

1995 ◽

Vol 5 (11) ◽

pp. 1895-1902 ◽

Cited By ~ 1

Author(s):

D J Nikolic-Paterson ◽

G H Tesch ◽

H Y Lan ◽

R Foti ◽

R C Atkins

Keyword(s):

Cell Proliferation ◽

Major Histocompatibility Complex ◽

Mhc Class Ii ◽

Cell Response ◽

Mesangial Cell ◽

Mesangial Cells ◽

Class Ii ◽

Glomerular Injury ◽

Histocompatibility Complex ◽

Mesangial Cell Proliferation

It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal injury in experimental glomerulonephritis. This study examined whether deoxyspergualin can modulate the mesangial cell response to glomerular injury. Antiglomerular basement membrane glomerulonephritis was induced in primed rats. Groups of five animals were treated with deoxyspergualin (5 mg/kg per day) or saline from Day 0 until being euthanized on Day 1, 7, 14, or 21. Deoxyspergualin treatment significantly inhibited mesangial cell proliferation (proliferating cell nuclear antigen expression) over the disease course as assessed by double immunohistochemistry staining (P < 0.001 versus saline treated) and reduced glomerular major histocompatibility complex (MHC) class II expression. To demonstrate if this was a direct action of deoxyspergualin, an in vitro system was studied. The addition of deoxyspergualin caused a time- and dose-dependent inhibition of [3H]thymidine uptake by cultured rat mesangial cells. Of particular interest was the finding that deoxyspergualin inhibited the de novo cell surface expression of MHC class II antigens after interferon-gamma stimulation. However, deoxyspergualin did not prevent the cytoplasmic accumulation of MHC class II molecules, indicating that the drug interfered with a posttranslational event in MHC class II processing and/or assembly. Deoxyspergualin was not a general inhibitor of mesangial cells, and it had no effect on constitutive or lipopolysaccharide-induced transforming growth factor beta 1 expression. In conclusion, deoxyspergualin has been shown to inhibit the mesangial cell response to glomerular injury. This novel mode of action may provide an additional therapeutic benefit in the treatment of proliferative forms of glomerulonephritis.

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

Journal of the American Society of Nephrology ◽

10.1681/asn.v10122606 ◽

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.

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