Intracellular Regulation of Inflammation

Kidney International (1999) 56, S70–S75; doi:10.1046/j.1523-1755.1999.07118.x

Atherogenic lipoproteins and tyrosine kinase mitogenic signaling in mesangial cells

Vaijinath S Kamanna, Babu V Bassa, Nosratola D Vaziri and Daeyoung D Roh

Nephrology Section, Department of Veterans Affairs Medical Center, Long Beach, and the Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California, USA

Correspondence: Vaijinath S. Kamanna, Ph.D, Nephrology Research Laboratories (151), Department of Veterans Affairs Medical Center, 5901 East Seventh Street, Long Beach, California 90822, USA

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Abstract

Atherogenic lipoproteins and tyrosine kinase mitogenic signaling in mesangial cells.

Background

 

Mesangial hypercellularity is a critical early histopathological finding seen in human and experimental glomerular diseases. Hyperlipidemia and the glomerular deposition of atherogenic lipoproteins [for example, low-density lipoprotein (LDL) and its oxidized variants, minimally oxidized/modified LDL (mm-LDL)] are commonly associated with mesangial hypercellularity and the development of glomerular disease. This article reviews signal transduction pathways involved in cell proliferation and provides evidence for the participation of atherogenic lipoproteins in intracellular signaling pathways for mesangial cell proliferation. The mitogenic intracellular signaling pathways are regulated by the activation of a series of transmembrane and cytoplasmic protein tyrosine kinases that converge into the activation of Ras and downstream mitogen-activated protein (MAP) kinase. Activated MAP kinase, through translocating into the nucleus and the activation of various transcription factors and proto-oncogenes, regulates cellular proliferation.

Methods

 

Murine mesangial cells were stimulated with LDL and mm-LDL and were analyzed for the tyrosine kinase activity, phosphorylation of membrane proteins, activation of Ras and MAP kinase, and cell proliferation.

Results

 

The results indicated that the stimulation of mesangial cells with LDL and, with greater activity, mm-LDL induced the phosphorylation of membrane platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors, activated Ras, and resulted in sustained (up to 24 hr) activation of MAP kinase. LDL/mm-LDL–mediated mesangial cell proliferation and MAP kinase activation were dependent on the activation of tyrosine kinases.

Conclusions

 

We suggest that the accumulation of LDL and more potently its oxidized forms within the glomerulus, through the activation of membrane receptor tyrosine kinases, activate the Ras and MAP kinase signaling cascade leading to DNA synthesis and subsequent cell proliferation.

Keywords:

glomerular disease, low-density lipoprotein, mesangial hypercellularity

Abbreviations:

ECM, extracellular matrix; EGF, epidermal growth factor; LDL, low density lipoprotein; LPC, lysophosphatidylcholine; MAP, mitogen-activated protein; MEK, MAP kinase kinase; mm-LDL, minimally oxidized/modified LDL; PDGF, platelet-derived growth factor; PKC, protein kinase C; PTK, protein tyrosine kinase; SH2, src homology 2

Previous studies aimed at understanding the physiology and pathophysiology of the glomerulus have revealed an apparent increase in intraglomerular mesangial cell number in the early phases of many glomerular diseases characterized by progressive glomerulosclerosis1. Human and experimental glomerular diseases that appear to support these sequence of events, namely increased mesangial cell number followed by glomerulosclerosis, include diabetic nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, and experimental models of anti-Thy-1–induced mesangial proliferative nephritis, puromycin aminonucleoside-induced nephrosis, and remnant kidney glomerular hypertension1,2. The current understanding favors the premise that the increased mesangial cells in the early phases of glomerular disease may influence the synthesis and deposition of extracellular matrix (ECM) proteins, leading eventually to sclerosis and renal failure. Indeed, such an association and/or link between proliferation of mesangial cells and subsequent ECM deposition has been observed in several experimental glomerulonephritis models, and the administration of platelet-derived growth factor (PDGF), a known mitogen, to experimental animals stimulated both mesangial cell proliferation and subsequent ECM expansion1,2. Experimental maneuvers that decrease glomerular cellular proliferation in control or anti-Thy-1–induced glomerulonephritis rats have also resulted in a relative decrease in ECM [reviewed in2. Taken together, these studies support the hypothesis that dysregulated glomerular mesangial cell mitogenesis may serve as one of the major pathobiological prerequisite factors for the early development and/or all phases of progressive glomerular disease.

Although the precise cellular and molecular mechanisms associated with mesangial hypercellularity in diverse glomerular diseases are not clearly defined, the stimuli for mesangial cell proliferation in response to glomerular injury have been attributed to multiple factors, including growth factors, inflammatory mediators, immune complexes, and complement components [reviewed in1,2,3. These factors involved in mesangial hypercellularity may be derived from intrinsic glomerular cells, acting in an autocrine or short-term paracrine manner, or from infiltrating inflammatory cells. In addition to these endogenous mediators, metabolic abnormalities or putative products generated by the metabolic derangement have also been suggested in the pathogenesis of glomerular disease. In this regard, a growing body of evidence indicates that abnormalities in lipid and atherogenic lipoprotein metabolism play an important pathobiological role in the development of glomerular disease [reviewed in4,5. In this article, we review recent developments in lipid-mediated pathobiological events of glomerular injury (with special emphasis on mesangial cell proliferation) and provide evidence to suggest that atherogenic lipoproteins, by modulating protein tyrosine kinase (PTK)-Ras–mediated signaling events, regulate mesangial cell proliferation.

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ROLE OF CHOLESTEROL AND ATHEROGENIC LIPOPROTEINS IN MESANGIAL CELL PROLIFERATION, EXTRACELLULAR MATRIX DEPOSITION, AND THE DEVELOPMENT OF GLOMERULAR INJURY

A causal relationship between hyperlipidemia and glomerular disease has long been recognized in hyperlipidemic experimental models [reviewed in4,5. Furthermore, recent studies from our and other laboratories have demonstrated multiple abnormalities in hepatic cholesterol and low-density lipoprotein (LDL) metabolism in human and experimental models of nephrosis and chronic renal failure and provided cellular and molecular mechanisms by which atherogenic lipoproteins facilitate cytokine-mediated monocyte infiltration into the glomerulus (abstract; Ha et al, J Am Soc Nephrol 6:830A, 1995)4,5,6,7,8. In addition to the increased systemic concentrations of atherogenic lipoproteins (for example, LDL), recent studies have indicated a pathological accumulation of lipids, LDL, and oxidized variants of LDL within the glomerulus of diverse human and experimental renal diseases9,10. Increased mesangial deposition of apolipoprotein (apo) B and/or E (major proteins of LDL) seen in patients with primary and secondary glomerular disease was associated with mesangial hypercellularity, increased urinary protein excretion, and the development of glomerulosclerosis11. Because mesangial hypercellularity and ECM deposition are common histological abnormalities (in addition to enhanced monocyte infiltration) in hyperlipidemia-induced experimental glomerular disease [reviewed in4,5, it has been thought that alterations in lipids and lipoproteins may have detrimental effects on mesangial cell proliferation and associated events. In support of this premise, recent studies using cultured mesangial cells provided direct evidence for the mitogenic effects of LDL on mesangial cell proliferation12,13.

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SIGNAL TRANSDUCTION PATHWAYS FOR CELL PROLIFERATION

The intracellular signaling pathways involved in cell proliferation generally proceed in an orderly fashion by generating early multiple intracellular protein phosphorylation signals in the membrane and cytosol, and within minutes, the mitogenic signal is propagated into the nucleus for DNA synthesis and cell multiplication. As noted in a simplified established model of mitogenic signal transduction paradigm Figure 1, cellular mitogenic stimulus (for example, growth factors, serum, or possibly other endogenous mitogenic metabolic products) can lead to the autophosphorylation and activation of intrinsic tyrosine kinase activity of specific membrane receptors, which, in turn, serves as high-affinity binding sites for the Src homology 2 (SH2) domain sequences that are encoded in different proteins [reviewed in14. Src homologous and collagen (Shc) and growth factor receptor-bound protein 2 (Grb2) adaptor proteins, containing SH2 domains, through phosphorylation by membrane receptors, interact with son of sevenless, an exchange catalyst that stimulates GDP dissociation from Ras, allowing the GTP binding and activation of Ras. The activated Ras associates with the N-terminal regulatory domain of Raf protein kinases, leading to the activation of Raf kinase. Raf has been shown to be an integrator of signals received from various pathways, including receptor tyrosine kinase and upstream serine-threonine kinases such as protein kinase C (PKC), and through activating MAP kinase kinase (MEK) stimulates mitogen-activated protein (MAP) kinase cascade. The activated cytoplasmic MAP kinase has been thought to translocate into the nucleus and activate various transcription factors and proto-oncogenes associated with cell growth and proliferation. Additionally, multiple signaling cascade including PKC, PTK, and G-protein–coupled receptors may interact to activate Ras-MAP kinase cascade Figure 1. In late G1, the mitogenic signals discussed earlier here converge with cyclin/cyclin-dependent protein kinases that regulate subsequent cell multiplication.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Signal transduction paradigm for cell proliferation. Cellular mitogenic stimulus can induce the autophosphorylation and activation of intrinsic tyrosine kinase activity of specific membrane receptors, which, in turn, can sequentially activate Ras, Raf, and MAP kinase. The activated cytoplasmic MAP kinase translocates into the nucleus and activates various transcription factors and proto-oncogenes associated with cell proliferation. PKC and G-protein–mediated events can also activate MAP kinase signaling. Atherogenic lipoproteins, by activating specific membrane receptors, may induce the activation of Ras-MAP kinase signaling.

Full figure and legend (54K)

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ROLE OF LIPIDS AND LIPOPROTEINS IN INTRACELLULAR SIGNALING

The role of lipids and atherogenic lipoproteins in intracellular signaling events for various cellular responses in glomerular mesangial cells is not known. However, in non-glomerular cells, the major signal transduction events associated with LDL, oxidized LDL (ox-LDL), or lysophosphatidylcholine (LPC, a major component of ox-LDL) have been attributed to the stimulation of phosphoinositide hydrolysis and activation of PKC15. Cholesterol enrichment of smooth muscle cells or interaction of ox-LDL with aortic endothelial cells is shown to inhibit the expression of Gi proteins, and the attenuation of endothelial-derived relaxation by LDL or LPC were associated with Gi-protein–mediated pathways16,17. Although the effect of cholesterol enrichment on cell proliferation is not clearly known, the inhibition of cholesterol synthetic pathway by HMG-CoA reductase inhibitors (for example, lovastatin) has been shown to inhibit cell proliferation in various cell types, including mesangial cells18. The mechanism of action of HMG-CoA reductase inhibitors on cell proliferation has been attributed to the inhibition of farnesol synthesis and associated isoprenylation of Ras proteins, important signaling molecules involved in cell proliferation18. Additionally, a growing number of studies have emerged to demonstrate the participation of other potent lipids (for example, phosphatidic acid, lysophosphatidic acid, glycerolipids, sphingolipids, and arachidonic acid/its metabolites) in PKC, G protein, and/or mitogenic signaling [reviewed in19. As summarized later here, we have shown that LDL and its oxidized variants can activate specific tyrosine kinase-MAP kinase signaling cascade involved in mesangial cell proliferation.

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STUDIES ON THE EFFECT OF ATHEROGENIC LIPOPROTEINS ON PROTEIN TYROSINE KINASE-MEDIATED INTRACELLULAR SIGNALING IN MESANGIAL CELLS

Using murine mesangial cells (stably transformed with SV-40; American Type Culture Collection, Rockville, MD, USA) as an in vitro model system, the following subsections describe the summary of our studies that examined the effect of LDL, minimally modified/oxidized LDL (mm-LDL, a proposed potent oxidized form of LDL within the vascular or glomerular tissue), and LPC on specific PTKs, Ras, and MAP kinase signaling pathways, and the involvement of PTKs in mesangial cell proliferation (abstract; Kamanna et al, J Am Soc Nephrol 8:2042, 1997)20,21.

Role of atherogenic lipoproteins in mesangial cell proliferation: Involvement of protein tyrosine kinase-dependent mechanisms

Incubation of quiescent mesangial cells with either LDL or mm-LDL for 24 hours dose-dependently (2.5 to 20 mug/ml) induced the incorporation of 3H-thymidine, as an index of increased DNA synthesis and cell proliferation (abstract; Kamanna et al, J Am Soc Nephrol 8:2042, 1997)20. The effect of mm-LDL was 2.1- to 2.8-fold greater when compared with controls Table 1. To understand the possible involvement of PTKs in LDL/mm-LDL–mediated cell proliferation, additional DNA synthesis studies were done using specific PTK inhibitors (for example, genistein and herbimycin). Preincubation of mesangial cells with either genistein (25 mug/ml) or herbimycin (10 mu M) for two hours blocked LDL/mm-LDL (10 mug/ml)–induced mesangial cell proliferation, suggesting the involvement of PTK-mediated signaling mechanisms Table 1. Additional studies indicated that both LDL and mm-LDL (10 mug/ml) increased cell membrane PTK activity (as determined by an assay kit using a synthetic peptide of 12 amino acids surrounding tyrosine phosphorylation site in pp60src, specific for epidermal growth factor (EGF) receptor; Life Technologies, GIBCO BRL products, Grand Island, NY, USA) by 14 and 36%, respectively ( Table 1; abstract; Kamanna et al, J Am Soc Nephrol 8:2042, 1997).


Effect of LDL/mm-LDL on cellular protein phosphorylation profile and identification of specific phosphorylated membrane proteins

Because PTK-mediated mitogenic signaling occurs through phosphorylation of upstream membrane and/or cytoplasmic proteins Figure 1, we examined the effect of LDL/mm-LDL on the possible phosphorylation of cellular/membrane proteins. Preliminary studies indicated that the stimulation of mesangial cells with LDL and mm-LDL (5 to 25 mug/ml), as early as five minutes, markedly induced the phosphorylation of cellular proteins of higher molecular weight proteins (150 to 200 kDa) and some modest phosphorylation of lower molecular weight proteins (40 to 60 kDa; Table 1, as assessed by Western blot: 7.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting with antiphosphotyrosine). mm-LDL had a twofold to threefold greater effect. We reasoned that the higher molecular weight phosphorylated proteins in the range of 150 to 200 kDa may be one or more membrane receptors (for example, PDGF receptor, EGF receptor). The data indicated that LDL and mm-LDL (10 mug/ml) induced the phosphorylation of PDGF and EGF receptors (as early as 5 to 60 min, as measured by in vivo32Pi-labeling: sodium dodecyl sulfate-polyacrylamide gel electrophoresis of PDGF/EGF receptor-immunoprecipitates, and autoradiography; abstract; Kamanna et al, J Am Soc Nephrol 8:2042, 1997). Because LDL/mm-LDL–induced signaling occurred within 3 to 15 minutes of stimulation, it is very unlikely that the effect of LDLs could be due to growth factors secreted into the media. In fact, stimulation of mesangial cells with LDLs for 10 to 30 minutes had no significant effect on growth factor secretion.

Effect of LDL/mm-LDL on Ras and mitogen-activated protein kinase activation: participation of protein tyrosine kinase or Gi-proteins

As LDL/mm-LDL activated the upstream membrane receptor phosphorylation, additional studies were performed to examine the impact on downstream Ras (measured by association of GTP with immunoprecipitated p21Ras) and MAP kinase (assessed by immunoprecipitation and kinase assay using myelin basic protein as a substrate) signaling. Both LDL and mm-LDL (5 to 25 mug/ml) stimulated MAP kinase activity (10 to 30 min and persisted up to 24 hr)20, and the effect of mm-LDL was much higher than LDL Table 1. PTK inhibitors (genistein and herbimycin) blocked LDL/mm-LDL–induced MAP kinase activity. Pretreatment of cells with pertussis toxin (which inactivates Gi-proteins) had no effect on LDL-induced MAP kinase activation, indicating that Gi proteins may not be involved in LDL-mediated MAP kinase activation. The incubation of mesangial cells with mm-LDL (10 mug/ml) as early as 3 minutes and up to 10 minutes markedly stimulated the activation of Ras, and LDL had marginal stimulatory effects on Ras activation by 10 minutes of incubation ( Table 1; abstract; Kamann et al, J Am Soc Nephrol 8:2042, 1997)22. Because high-density lipoprotein (HDL, another major lipoprotein) had no effect on MAP kinase, the mitogenic effects appear to be specific for LDL.

Effect of lysophosphatidylcholine on mitogenic signaling

Lysophosphatidylcholine, one of the major components of oxidized variants of LDL, has been implicated for various cellular responses of oxidized LDL. We have shown that LPC (5 to 25 mu M) activated MAP kinase and PKC in mesangial cells within 5 to 15 minutes of stimulation Table 1. LPC-induced MAP kinase activation was significantly inhibited (but not completely) by prior cellular PKC inhibition, suggesting the participation of PKC and other additional signaling events21. LPC stimulated cell membrane PTK activity and markedly induced Ras activation within 2 to 10 minutes and sustained up to 60 minutes. Preincubation of mesangial cells with PTK inhibitor (genestein, 100 mu M), but not pertussis toxin, blocked LPC-induced MAP kinase activity21.

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CONCLUSIONS

We have provided evidence that LDL and more potently minimal oxidative modification of LDL (for example, mm-LDL) and its active component (for example, LPC) stimulated mesangial cell upstream membrane tyrosine receptor phosphorylation and Ras activation leading to the activation of downstream MAP kinase signaling involved in mesangial cell proliferation Figure 1. LDL/mm-LDL–mediated mesangial cell proliferation was dependent on PTK activation, as PTK inhibitors blocked mesangial cell DNA synthesis. Lipoprotein-mediated mitogenic signaling was not dependent on pertussis toxin-sensitive Gi-protein–related events. Although the cellular mechanisms by which atherogenic lipoproteins or their active components activate specific membrane and/or cytosolic mitogenic signaling are not known, several factors or processes may be proposed for the mitogenic signaling of atherogenic lipoproteins. For example, the cellular cholesterol deposition and/or the interaction of LDL and its oxidized forms, through membrane lipid-phase catalysis or causing perturbation in the lipid bilayer properties, may interact indirectly or directly with mitogenic membrane receptors, resulting in the phosphorylation and kinase activation22. The enhanced mitogenic signaling events of oxidized LDL or its components may be in part due to the impact of oxidative stress on cellular signaling. Additionally, the specific homology between cysteine-rich extracellular domains of growth factor receptors (for example, EGF receptor and PDGF receptor) to the NH2-terminal extracellular domain of LDL receptor may have some contributory role in the interaction of LDLs with membrane receptors leading to the aggregation/autophosphorylation and downstream events23. Thus, we propose that the accumulation of cholesterol and/or the interaction of LDL with cells, through modulating some of the previously noted mechanisms, may induce PTK-Ras-MAP kinase mitogenic signaling cascade associated with cell DNA synthesis and subsequent cell proliferation Figure 1.

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Acknowledgments

The cited studies from the authors' laboratories were supported by a Merit Review from the Department of Veterans Affairs and an Institutional Fellowship from the National Kidney Foundation of Southern California. The authors dedicate this article in memory of Dr. Michael A. Kirschenbaum, who departed us on June 21, 1997. We wish to thank Drs. Rama Pai and Hunjoo Ha for their assistance and input in proliferation studies.

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