Orth, Stephan R.

Viedt, Christiane

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Monocyte chemoattractant protein-1 (MCP-1) in the kidney: does itmore than simply attract monocytes?Christiane Viedt1 and Stephan R. Orth21Department of Internal Medicine, Division of Cardiology, Ruperto Carola University, Heidelberg, Germany and2Division of Nephrology and Hypertension, University Hospital of Berne (Inselspital), SwitzerlandKeywords: activator protein-1; intercellular adhesionmolecule-1; interleukin-6; monocyte chemoattractantprotein-1; nuclear factor-kB; tubular epithelial cellsMCP-1: a player in the pathogenesis ofprogression of renal diseasesThere is an increasing body of evidence that theCC chemokine monocyte chemoattractant protein-1(MCP-1) plays a major role in the pathogenesis ofprogression of renal failure. This is based on observa-tions both in various animal models of renal damageand in different types of human renal disease (forreview, see [1]). Locally produced MCP-1 seems to beparticularly involved in the initiation and progressionof tubulointerstitial damage. The latter has beendocumented in experiments using transgenic micewith nephrotic serum-induced nephritis: comparedwith wild-type mice, MCP-1-deficient mice exhibitless tubulointerstitial lesions, but they exhibit nodifferences in glomerular lesions [2]. There is, however,evidence that MCP-1 also plays a role in the progres-sion of glomerular lesions, since glomerular expressionof MCP-1 correlates with the degree of renal damagein inflammatory [3] and non-inflammatory [4] modelsof glomerular injury. Furthermore, in humans withcrescentic glomerulonephritis, MCP-1 is not onlyexpressed in tubular epithelial cells and leukocytesinfiltrating the tubulointerstitium, but also in crescentsand parietal epithelium [5]. In experimental crescenticglomerulonephritis, administration of antibodies toMCP-1 decreases the extent of proteinuria, reducesglomerulosclerosis and improves renal dysfunction [6].Of importance, a consistent increase of urinaryMCP-1 concentration is found in patients or animalsCorrespondence and offprint requests to: Stephan R. Orth,Department of Nephrology and Hypertension, University Hospitalof Berne (Inselspital), CH-3010 Berne, Switzerland.Email: stephan.orth@insel.chNephrol Dial Transplant (2002) 17: 2043–2047# 2002 European Renal Association–European Dialysis and Transplant Association2043Nephrol Dial Transplant (2002) 17: Editorial Commentswith a diseased kidney, and this correlates with thedegree of urinary albuminuprotein excretion and renaldamage [7–10]. In addition to mesangial cells, endo-thelial cells and infiltrating mononuclear cells [11,12],tubular epithelial cells [12,13] seem to be the majorsource of MCP-1 in urine. The increased production ofMCP-1 by tubular epithelial cells is due to: (i) stimula-tion by cytokines [14,15]; and (ii) exposure to urinaryproteins [16]. Both are mediators of progressive renaldamage [17].Interestingly, therapy with an angiotensin-convertingenzyme (ACE) inhibitor or an angiotensin II receptortype 1 (AT1) antagonist is able to abrogate the renalexpression of MCP-1 [18,19]. This may not only bedue to reduction of proteinuria. Rat mesangial cellsin vitro produce increasing amounts of MCP-1 inresponse to increasing external pressure, suggestingthat MCP-1 may be a mediator of the adverse effectsof intraglomerular hypertension [20]. The latter is animportant factor in the genesis of progressive glomerulardamage, which is attenuated by therapy with an ACEinhibitor or an AT1 receptor antagonist. Taken toge-ther, MCP-1 seems to be of pivotal importance inthe pathogenesis of progression of renal damage andfailure.To date, the classic perception of MCP-1 was thatits main property is the attraction of monocytesumacrophages. These inflammatory cells in turn secretecytokines and chemokines, fostering inflammation andfibrosis. Increased synthesis of cytokines and chemo-kines by infiltrating inflammatory cells and residentrenal cells has been documented in various forms ofglomerulonephritis and tubulointerstitial nephritis. Ithas been suggested that they are important mediatorsof progressive renal failure in vivo [1]. Recent data[21,22] indicate that the role of MCP-1 goes beyondthat of a simple chemoattractant protein.MCP-1 induces an inflammatory activation ofhuman tubular epithelial cellsRecent data from our group provide evidence thatincreased concentrations of MCP-1 in the diseasedkidney may be an important factor contributing per seto increased production of cytokines and adhesionmolecules. We demonstrated that MCP-1 specificallyactivates tubular epithelial cells in vitro [21], leadingto a time- and dose-dependent increase in secretionof the proinflammatory cytokine interleukin-6(IL-6) and expression of the intracellular adhesionmolecule-1 (ICAM-1) via Gi-protein-, protein kinaseC (PKC)- and intracellular Ca2q-dependent mechan-isms (Figure 1). MCP-1 activated: (i) the transcriptionfactor nuclear factor-kB (NF-kB), a transcriptionfactor commonly involved in inflammatory andimmune responses, and (ii) activating protein-1 (AP-1),a transcription factor involved in inflammatory andgrowth responses. Both NF-kB and AP-1 were involvedin the MCP-1-mediated induction of IL-6. In contrastto IL-6 release, MCP-1-induced ICAM-1 expressionwas predominantly dependent on NF-kB activation(Figure 2). IL-6 has been suggested to contribute toFig. 1. Scheme of the intracellular signalling pathways of MCP-1 in a human tubular epithelial cell.2044 Nephrol Dial Transplant (2002) 17: Editorial Commentsprogression of renal diseases [23,24] because its renalexpression correlates with the degree of mesangialhyperproliferation, tubular atrophy, and the intensityof interstitial infiltrates [25,26]. De novo expressionof the adhesion molecule ICAM-1 by tubular epithelialcells and increased expression by interstitial and glome-rular cells has been observed in different formsof glomerulonephritis, tubulointerstitial inflammationand renal allograft rejection [27]. Thus, the observedeffects of MCP-1 on tubular epithelial cells in vitromay be critical steps during progression in vivo.MCP-1 does not only exhibit direct effects ontubular epithelial cells, but also on another cell typethat plays a role in progressive renal damage, i.e.vascular smooth muscle cells [22]. Stimulation ofvascular smooth muscle cells with MCP-1 inducedproliferation and resulted in a concentration- and time-dependent release of IL-6. Similar to tubular epithelialcells, this effect was mediated via Gi-protein, PKC andNF-kB. MCP-1 also induced extracellular signal-regulated kinase (ERK), which, along with IL-6release, was Gi-protein-dependent. MCP-1-induced,proliferation of vascular smooth muscle cells, whichwas ERK-dependent. MCP-1 stimulated the bindingactivity of NF-kB and of AP-1. NF-kB was involved inIL-6 release by MCP-1, whereas proliferation wasdependent on AP-1, demonstrating that, as in tubularepithelial cells, MCP-1 induces differential activationof NF-kB and AP-1 in vascular smooth muscle cells.Thus, these latter data do not only propose a newmechanism for the proatherogenic effect of MCP-1in the progression of cardiovascular disease, but alsoimplicate MCP-1 as a factor leading to vasculardamage in the diseased kidney.Which receptor(s) is responsible for the mediationof effects of MCP-1 on human tubular epithelialcells?Chemokines exert their effects through binding toG-protein-coupled receptors on the surface of leukocytestargeted for activation and migration. These receptors,once activated, trigger a set of cellular reactions thatresult in inositol triphosphate formation, intracellularcalcium release, and PKC activation [28]. The classicMCP-1 receptors belong to the family of heptahelical,pertussis-sensitive, G-protein-coupled receptors [29].The MCP-1 receptor on tubular epithelial cells appearsto be coupled to Gi-protein activation [21]. Thesefindings are in accordance with our observations invascular smooth muscle cells [22], as well as data ofothers [29,30].As in leukocytes, MCP-1-induced up-regulation ofIL-6 synthesis and ICAM-1 expression by humantubular epithelial cells are dependent on PKC andintracellular Ca2q (Ca2qi ) [21]. Similarly, Schecteret al. [30] demonstrated that the induction of tissuefactor by MCP-1 in human vascular smooth musclecells required Ca2qi mobilization and that it was PKC-dependent. Therefore, although currently unproven,it is likely that MCP-1-signalling is mediated by theclassical PKC subgroups a, b or c.To date, in renal tissue of humans and experimentalanimals, expression of CCR1-5 mRNA transcriptswere detected only in infiltrating mononuclear cells.Two MCP-1 receptors, generated by alternative spli-cing and designated as CCR2A and -B, have beencloned in human monocytes [31]. On the basis ofour polymerase chain reaction and flow cytometryFig. 2. Scheme of the direct and indirect effects of MCP-1 on human tubular epithelial cells (TECs).2045Nephrol Dial Transplant (2002) 17: Editorial Commentsanalysis studies, the MCP-1 receptor on human tubu-lar epithelial cells is distinct from these two receptors[21]. Furthermore, the MCP-1 receptor on humantubular epithelial cells is also distinct from the CCR1,CCR3, CCR4 and CCR5 receptors. Antibodies againstCCR1–5 failed to inhibit the specific effects of MCP-1on tubular epithelial cells. However, binding studiesfor MCP-1 revealed that cultured human tubularepithelial cells express a MCP-1 binding protein onthe cell surface. The possibility that the effects ofMCP-1 on tubular epithelial cells are mediated via anendosome-lysosomal pathway was ruled out [21].Taken together, the above results implicate that it islikely that the MCP-1 receptor on human tubularepithelial cells is different from previously clonedCC chemokine receptors. The nature of the MCP-1receptor(s) on human tubular epithelial cells, whichseems to be Gi-protein coupled, remains to bedetermined (Figure 1).ConclusionMCP-1 can activate tubular epithelial cells directlyin vitro. This action of MCP-1 on a resident renal cellhad so far remained unknown, but had been des-cribed in cultured vascular smooth muscle cells [22,30].The MCP-1-mediated activation of tubular epithelialcells is consistent with the notion that MCP-1 contri-butes to tubulointerstitial inflammation, which is ahallmark of progressive renal disease [17]. Importantly,tubulointerstitial rather than glomerular damage cor-relates best with the loss of renal function and the riskof progression to end-stage renal failure. Actually,there is a strict correlation between tubular atrophy,interstitial fibrosis, the extent of interstitial infiltratesand renal dysfunction [32]. The direct effects of MCP-1on vascular smooth muscle cells [22] may not only beof importance in the progression of cardiovasculardamage in general, but also in the progression ofvascular lesions in the kidney, which could contributefurther to progression of renal failure.Previous studies focused on the role of MCP-1 inrenal inflammation and its induction of inflammatorysignals [1]. Our recent data suggest that MCP-1 is morethan just a chemoattractant. Rather, MCP-1 candirectly elicit an inflammatory response by inducingcytokine and adhesion molecule expression in thekidney. This is an important new mechanism in thepathogenesis of tubulointerstitial inflammation.Note added in proofKru¨ger et al. [33] recently reported that recipients of arenal allograft who are carriers of the MCP-1-2518(GuG) polymorphism, i.e. a genotype characterizedby increased production of MCP-1 by mononuclearcells, have a significantly reduced mean graft survivalcompared with the heterozygous (AuG) or wild-type(AuA) allele carriers. In contrast, carriers of the 64Imutation of the CCR2 receptor, a genotype whichpresumably alters CCR2 expression or function, hadno increase of mean renal allograft survival. Thesein vivo data support our in vitro findings [21], i.e.specific inflammatory activation of human tubularepithelial cells by MCP-1 despite the lack of CCR2receptors on these cells.References1. Segerer S, Nelson PJ, Schlo¨ndorff D. Chemokines, chemokinereceptors, and renal disease: from basic science to pathophy-siologic and therapeutic studies. J Am Soc Nephrol 2000;11: 152–1762. Tesch GH, Schwarting A, Kinoshita K et al. 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J Am Soc Nephrol 2002; 13: 2585–2589# 2002 European Renal Association–European Dialysis and Transplant Association2047Nephrol Dial Transplant (2002) 17: Editorial Comments

Monocyte chemoattractant protein‐1 (MCP‐1) in the kidney: does it more than simply attract monocytes?

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