Oxidative modification of low-density lipoproteins by mesangial cells.

Because hypercholesterolemia and mesangial cell proliferation may be important in the pathogenesis of glomerulosclerosis, the effects of low-density lipoprotein (LDL) on human mesangial cell proliferation were evaluated. Native LDL (20 to 200 micrograms/mL) caused a dose-dependent increase in (3H)thymidine incorporation and increased mesangial cell numbers over 96 h. The mitogenic effect of LDL was partially blocked by the inhibition of cytochrome P-450, but not by the inhibition of cyclooxygenase or lipoxygenase pathways. Higher LDL concentrations (1,000 to 2,000 micrograms/mL) inhibited (3H)thymidine incorporation and reduced cell numbers, possibly as a result of the oxidative modification of LDL, indicated by an increase in thiobarbituric reactive substances. This peroxidation of LDL involved superoxide, because superoxide dismutase and butylated hydroxytoluene prevented it, whereas hydroxyl radical scavengers were without effect. Native LDL subjected to chemical oxidation by copper sulfate also inhibited mesangial cell proliferation. These results suggest that low concentrations of LDL may stimulate human mesangial cell proliferation, which may, in turn, cause the production of reactive oxygen molecules. Moreover, the oxidative modification of LDL may mediate the toxic effects of high LDL concentrations on human mesangial cells.

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

Journal of the American Society of Nephrology ◽

10.1681/asn.v881247 ◽

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.

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Interactions of Hydrogen Peroxide with Interleukin-6 and Platelet-Derived Growth Factor in Determining Mesangial Cell Growth: Effect of Repeated Oxidant Stress

Clinical Science ◽

10.1042/cs0850747 ◽

1993 ◽

Vol 85 (6) ◽

pp. 747-751 ◽

Cited By ~ 10

Author(s):

R. J. D'Souza ◽

H. M. Phillips ◽

P. W. Jones ◽

R. C. Strange ◽

G. M. Aber

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Interleukin 6 ◽

Mesangial Cell ◽

Thymidine Incorporation ◽

Mesangial Cells ◽

Platelet Derived Growth Factor ◽

Growth Effect ◽

Cell Counts ◽

Mesangial Cell Proliferation

1. This study examined the influence of H2O2, interleukin-6 and platelet-derived growth factor on the proliferation of rat mesangial cells. Mesangial cells were exposed to either a single pulse or three daily pulses of H2O2 (10−8-10−4 mol/l), alone or in combination with interleukin-6 (5 ng/ml) and/or platelet-derived growth factor (10 ng/ml). Proliferation was assessed after 24 h and 72 h of incubation using [3H]thymidine incorporation and cell counts. 2. Although one pulse of H2O2 had no significant effect on mesangial cell proliferation, three daily pulses of 10−6 mol/l H2O2 resulted in a significant increase in [3H]thymidine incorporation of 31 (52.6, 10.3)% (median and 75th-25th interquartile range) (P <0.001). Both interleukin-6 and platelet-derived growth factor were also mitogenic to mesangial cells, [3H]thymidine incorporation increasing by 19 (36.7, −6.7)% (P <0.05) and 53.5 (107, 21.9)% (P <0.001), respectively. The mitogenic effect of interleukin-6 was enhanced by 10−6 mol/l H2O2 [49.9 (77.7, 12.3)%] (P <0.01), whereas the addition of 10−6 mol/l H2O2 to platelet-derived growth factor resulted in a summated increase in [3H]thymidine incorporation of 82.7 (113, 57.4)% (P <0.001). Incubation with all three substances simultaneously resulted in down-regulation of growth compared with H2O2 plus platelet-derived growth factor by 55.4 (77.7, 103)% (P <0.05). 3. These findings suggest that reactive oxygen species may play a major role in determining the mesangial cell proliferation that occurs in certain forms of glomerulonephritis, acting either alone or in combination with other growth factors.

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Ramipril Inhibits in vitro Human Mesangial Cell Proliferation and Platelet-Derived Growth Factor Expression

Nephron Experimental Nephrology ◽

10.1159/000020606 ◽

1999 ◽

Vol 7 (3) ◽

pp. 229-235 ◽

Cited By ~ 9

Author(s):

Giuseppe Grandaliano ◽

Elena Ranieri ◽

Raffaella Monno ◽

Loreto Gesualdo ◽

Francesco P. Schena

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Mesangial Cell ◽

Platelet Derived Growth Factor ◽

Human Mesangial Cell ◽

Mesangial Cell Proliferation ◽

Factor Expression ◽

Growth Factor Expression

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Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion

Nephrology Dialysis Transplantation ◽

10.1093/ndt/14.1.58 ◽

1999 ◽

Vol 14 (1) ◽

pp. 58-63 ◽

Cited By ~ 94

Author(s):

I Hauser

Keyword(s):

Cell Proliferation ◽

Mycophenolate Mofetil ◽

Mesangial Cell ◽

Human Mesangial Cell ◽

Mesangial Cell Proliferation

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

International Journal of Molecular Sciences ◽

10.3390/ijms21197003 ◽

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.

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

AJP Cell Physiology ◽

10.1152/ajpcell.00387.2013 ◽

2014 ◽

Vol 306 (11) ◽

pp. C1089-C1100 ◽

Cited By ~ 18

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.

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