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• W1999944709 abstract "Macrophages and progressive tubulointerstitial disease. In chronic renal disease, tubulointerstitial inflammation and injury is associated with infiltrating macrophages. As a consequence of primary injury, proteinuria, chronic hypoxia, and glomerular-derived cytokines may all differentially modulate the expression of factors that promote macrophage recruitment. In addition to adhesion molecules and chemokines, products of complement system and renin-angotensin system activation may direct this process. Once present at interstitial sites, macrophages interact with resident cells and extracellular matrix to generate a proinflammatory microenvironment that amplifies tissues injury and promotes scarring. There is now increasing evidence for the efficacy of interventions directed against factors that recruit, activate, or are produced by macrophages. A detailed understanding of the biology of this area may lead to the further development of therapies that will improve the outcome of renal disease. Macrophages and progressive tubulointerstitial disease. In chronic renal disease, tubulointerstitial inflammation and injury is associated with infiltrating macrophages. As a consequence of primary injury, proteinuria, chronic hypoxia, and glomerular-derived cytokines may all differentially modulate the expression of factors that promote macrophage recruitment. In addition to adhesion molecules and chemokines, products of complement system and renin-angotensin system activation may direct this process. Once present at interstitial sites, macrophages interact with resident cells and extracellular matrix to generate a proinflammatory microenvironment that amplifies tissues injury and promotes scarring. There is now increasing evidence for the efficacy of interventions directed against factors that recruit, activate, or are produced by macrophages. A detailed understanding of the biology of this area may lead to the further development of therapies that will improve the outcome of renal disease. Over 30 years ago, Risdonet al first described the association between the degree of renal impairment and the extent of tubulointerstitial damage in patients with glomerular disease[1Risdon R.A. Sloper J.C. De Wardener H.E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis.Lancet. 1968; 2: 363-366Abstract PubMed Google Scholar]. Subsequent studies have shown that this relationship is a major determinant of progression to end-stage renal failure (ESRF), and that interstitial inflammation has a central role in this process. As the interstitial macrophage is involved in both the initiation and continuation of this inflammatory response, a detailed knowledge of the role of these cells in situ may lead to the development of new treatments. Here we review our current understanding of the mechanisms that recruit monocytes to the interstitium, how interactions between the differentiated macrophage and other components of the local microenvironment promote progressive injury, and how current and future therapies may modulate these processes. For the purpose of this review, both monocytes and differentiated interstitial macrophages will be denoted by Mφ. Tubulointerstitial (TI) disease is common to all chronic progressive renal diseases, irrespective of the initial trigger or site of injury. It is characterized by inflammatory cell infiltrates, loss of peritubular capillaries, atrophy of tubules, and interstitial scarring. The extent of disease on renal biopsy inversely correlates with renal function and accurately predicts renal prognosis[2Nath K.A. The tubulointerstitium in progressive renal disease.Kidney Int. 1998; 54: 992-994Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. Morphometric studies indicate that glomerular and tubulointerstitial injury is interdependent: thus, in glomerulonephritis, damage of a single nephron may progress from initial glomerular injury to peritubular and interstitial inflammation, tubular atrophy, and interstitial scarring[2Nath K.A. The tubulointerstitium in progressive renal disease.Kidney Int. 1998; 54: 992-994Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. This local inflammatory response may then involve adjacent tubules and so initiate or potentiate upstream glomerular injury. As damage progresses, remaining glomeruli compensate through the development of capillary hypertension, and glomerulosclerosis develops independent of the primary injury (reviewed in[3Taal M.W. Omer S.A. Nadim M.K. Mackenzie H.S. Cellular and molecular mediators in common pathway mechanisms of chronic renal disease progression.Curr Opin Nephrol Hypertens. 2000; 9: 323-331Crossref PubMed Scopus (26) Google Scholar]). Thus, nephron loss as a consequence of secondary interstitial inflammation may progress to ESRF. A prominent feature throughout this process is the presence of leukocytes at sites of injury. In the normal kidney there are small numbers of interstitial leukocytes. These are predominantly Mφ, although T cells are also present. In human glomerular disease there are increased numbers of Mφ and T cells at interstitial sites; most studies report that T cells predominate, and the majority of these are CD4+, although there is considerable variation between these analysesTable 1. These results should be interpreted with caution, however, as Mφ enumeration in these studies was performed by immunohistochemistry (IHC) with primary antibodies directed against the surface antigen CD14. As the expression of this antigen varies with the maturity and activation status of the cell, Mφ numbers have probably been underestimated.Table 1Interstitial Mφ and T-cell ratios in renal disease: Published series with 10+ patientsNephropathy (Patient number)ReferenceT cell: MφCD4: CD8Lupus (35)4Alexopoulos E. Seron D. Hartley R.B. Cameron J.S. Lupus nephritis: Correlation of interstitial cells with glomerular function.Kidney Int. 1990; 37: 100-109Abstract Full Text PDF PubMed Google Scholar1.51.5IgA (34)5Alexopoulos E. Seron D. Hartley R.B. et al.The role of interstitial infiltrates in IgA nephropathy: a study with monoclonal antibodies.Nephrol Dial Transplant. 1989; 4: 187-195PubMed Google Scholar0.92.1Non-cresc IgA (18)6Li H.L. Hancock W.W. Hooke D.H. et al.Mononuclear cell activation and decreased renal function in IgA nephropathy with crescents.Kidney Int. 1990; 37: 1552-1556Abstract Full Text PDF PubMed Google Scholar2.41.4Cresc IgA (5)1.11.3Memb (13)7Hooke D.H. Gee D.C. Atkins R.C. Leukocyte analysis using monoclonal antibodies in human glomerulonephritis.Kidney Int. 1987; 31: 964-972Abstract Full Text PDF PubMed Google Scholar2.80.5FGS (13)1.41.9DN (9)41IgA (18)2.41.4Lupus (13)2.71.9Cresc GN (14)2.91MPGN (8)2.61.4FPGN (10)31.2Memb (36)8Alexopoulos E. Seron D. Hartley R.B. et al.Immune mechanisms in idiopathic membranous nephropathy: The role of the interstitial infiltrates.Am J Kidney Dis. 1989; 13: 404-412Abstract Full Text PDF PubMed Google Scholar0.82.2MPGN (17)9Naiker I.P. Ramsaroop R. Somers S.R. et al.Leukocyte analysis of tubulointerstitial nephritis in primary membranoproliferative glomerulonephritis.Am J Kidney Dis. 1996; 27: 316-320Abstract Full Text PDF PubMed Google Scholar5.1-Cresc GN (9)10Markovic-Lipkovski J. Muller C.A. Risler T. et al.Association of glomerular and interstitial mononuclear leukocytes with different forms of glomerulonephritis.Nephrol Dial Transplant. 1990; 5: 10-17Crossref PubMed Google Scholar162FGS (11)9.11.4MPGN (7)3.81.6Cresc GN (3)11Boucher A. Droz D. Adafer E. Noel L.H. Characterization of mononuclear cell subsets in renal cellular interstitial infiltrates.Kidney Int. 1986; 29: 1043-1049Abstract Full Text PDF PubMed Google Scholar1.11.5Lupus (7)0.81.3Abbreviations are: Cresc, crescentic; Memb, membranous nephropathy; FGS, focal glomerulosclerosis; DN, diabetic nephropathy; MPGN, membranoproliferative glomerulonephritis; FPGN, focal proliferative glomerulonephritis. Ratios extrapolated from published data where cell numbers had been expressed as number per mm2 tissue viewed. Open table in a new tab Abbreviations are: Cresc, crescentic; Memb, membranous nephropathy; FGS, focal glomerulosclerosis; DN, diabetic nephropathy; MPGN, membranoproliferative glomerulonephritis; FPGN, focal proliferative glomerulonephritis. Ratios extrapolated from published data where cell numbers had been expressed as number per mm2 tissue viewed. Only a small fraction of leukocytes in the normal kidney comprise B cells, natural killer (NK) cells, and neutrophils. In disease states they represent less than 10% of total infiltrating cells, although in proliferative glomerulonephritides, this proportion may be higher[7Hooke D.H. Gee D.C. Atkins R.C. Leukocyte analysis using monoclonal antibodies in human glomerulonephritis.Kidney Int. 1987; 31: 964-972Abstract Full Text PDF PubMed Google Scholar],[10Markovic-Lipkovski J. Muller C.A. Risler T. et al.Association of glomerular and interstitial mononuclear leukocytes with different forms of glomerulonephritis.Nephrol Dial Transplant. 1990; 5: 10-17Crossref PubMed Google Scholar]. Studies in animal models indicate that Mφ are the dominant infiltrating cell in the initiation and progression of injury in chronic renal disease (reviewed in[12Rodriguez-Iturbe B. Pons H. Herrera-Acosta J. Johnson R.J. Role of immunocompetent cells in nonimmune renal diseases.Kidney Int. 2001; 59: 1626-1640Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]). Strategies that limit disease progression in his setting include: (1) the systemic depletion of Mφ; (2) inhibition of proinflammatory cytokines that both activate and are produced by activated Mφ; and (3) the blocking of factors that promote the recruitment of Mφ to tissue sites. While T cells almost certainly have an important role in progressive injury in situ in chronic TI disease, this has not been clearly defined to date, and factors that promote their recruitment and activation require further investigation. The use of T-cell-deficient mice in a number of models of progressive renal disease did not, however, prevent the development of renal injury[13Eddy A.A. Interstitial nephritis induced by protein-overload proteinuria.Am J Pathol. 1989; 135: 719-733PubMed Google Scholar, 14Eddy A.A. Mcculloch L. Liu E. Adams J. A relationship between proteinuria and acute tubulointerstitial disease in rats with experimental nephrotic syndrome.Am J Pathol. 1991; 138: 1111-1123PubMed Google Scholar, 15Shappell S.B. Gurpinar T. Lechago J. et al.Chronic obstructive uropathy in severe combined immunodeficient (SCID) mice: Lymphocyte infiltration is not required for progressive tubulointerstitial injury.J Am Soc Nephrol. 1998; 9: 1008-1017PubMed Google Scholar]. Resident and infiltrating Mφ play a central role in innate immune protection both through the clearance of infective pathogens and through the repair of tissue injury that occurs, in part, as a consequence of this response. For example, the initial response of Mφ to bacterial infection is cytotoxic and proinflammatory; then, on control of the infection, Mφ phagocytoze cellular debris and apoptotic bodies and begin tissue repair. However, in many noninfective renal diseases associated with Mφ infiltrates, although the primary cause may abate, interstitial inflammation and TI injury worsens[12Rodriguez-Iturbe B. Pons H. Herrera-Acosta J. Johnson R.J. Role of immunocompetent cells in nonimmune renal diseases.Kidney Int. 2001; 59: 1626-1640Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. Direct damage to resident cells is caused through the generation by Mφ of radical oxygen species (ROS), nitric oxide (NO), complement factors, and proinflammatory cytokines ([12Rodriguez-Iturbe B. Pons H. Herrera-Acosta J. Johnson R.J. Role of immunocompetent cells in nonimmune renal diseases.Kidney Int. 2001; 59: 1626-1640Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]; seeFigure 1). Mφ can also affect supporting matrix and vasculature through the expression of metalloproteinases and vasoactive peptides. Resident interstitial fibroblasts and myofibroblasts proliferate in response to Mφ-derived profibrogenic cytokines, and their number correlates with the subsequent formation of a scar and renal decline[16Roberts I.S. Burrows C. Shanks J.H. et al.Interstitial myofibroblasts: Predictors of progression in membranous nephropathy.J Clin Pathol. 1997; 50: 123-127Crossref PubMed Google Scholar]. These cells are a primary source of the extracellular matrix (ECM) proteins that accumulate to form a scar. They may be derived from transdifferentiated tubular epithelial cells, a process promoted by profibrogenic cytokines, including transforming growth factor-β (TGF-β) expressed by Mφ, and also by tubular epithelial cells as a consequence of Mφ-tubular cell interactions (reviewed in[17Lan H.Y. Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells.Curr Opin Nephrol Hypertens. 2003; 12: 25-29Crossref PubMed Scopus (171) Google Scholar]). The role of TGF-β has been studied in detail. It promotes the production of all the major matrix proteins by fibroblasts, inhibits expression of matrix degrading plasminogen-activator inhibitor (PAI), and increases the activity of tissue inhibitors of metalloproteinases (TIMPS). In a rat model of progressive proteinuric renal disease, interstitial Mφ produced TGF-β, and levels correlated with interstitial inflammatory infiltration[18Eddy A.A. Protein restriction reduces transforming growth factor-beta and interstitial fibrosis in nephrotic syndrome.Am J Physiol. 1994; 266: F884-893PubMed Google Scholar]. Although interstitial Mφ proliferate in situ, their increase in numbers at sites of secondary TI disease primarily reflects the recruitment of circulating Mφ, which largely occurs at the level of postcapillary venulesFigure 2. Endothelial cells (EC) and the subendothelial environment at sites of disease variably demonstrate constitutive, up-regulated, and de novo expression of a number of ligands that direct this process. The binding of these molecules to counter-receptors on the surface of Mφ promotes the phenotypic and ultrastructural changes required for cell transmigration. There are several obligate steps in this process, each of which is directed by specific families of molecules (reviewed in[19Brady H.R. Leukocyte adhesion molecules and kidney diseases.Kidney Int. 1994; 45: 1285-1300Abstract Full Text PDF PubMed Google Scholar]). Following their initial contact with the luminal surface of venules, the cells roll through the rapid association and dissociation of EC selectins and Mφ counter ligands (Figure 2,Table 2). These interactions are strong enough to resist shear stress, thereby slowing the cells sufficiently to permit sampling of the rich microenvironment at the EC surface (reviewed in[20Tam F.W. Role of selectins in glomerulonephritis.Clin Exp Immunol. 2002; 129: 1-3Crossref PubMed Scopus (0) Google Scholar]).Table 2Adhesion molecules involved in monocyte traffickingStage of traffickingFamilyIndividual membersCD numberLigandsRollingSelectinsP-SelectinCD62PPSGL-1, L-selectinE-SelectinCD62EESL-1, PSGL-1,L-selectinL-SelectinCD62LsLex, GlyCAM-1Firm adhesionIntegrinsLFA-1CD11a/Cd18ICAM-1VLA-4CD49d/CD29VCAM-1Transendothelial migrationIntegrinsLFA-1CD11a/Cd18ICAM-1VLA-4CD49d/CD29VCAM-1Ig-SFPECAM-1CD31PECAM-1JAM-1LFA-1Glyco- proteinCD99CD99Subendothelial migrationIntegrinsVLA-4CD49d/CD29FN (CS-1)VLA-5CD49e/CD29FN (RGD)Ig-SFPECAM-1CD31Basement membrane componentsAbbreviations are: FN, fibronectin; Ig-SF, immunoglobulin superfamily. Open table in a new tab Abbreviations are: FN, fibronectin; Ig-SF, immunoglobulin superfamily. Three selectins have been identified. P-selectin is stored preformed in Weibel-Palade bodies, and is rapidly translocated to EC surface on activation (by proinflammatory cytokines or histamine); this expression is transient and decreases in minutes. E-selectin expression is largely restricted to EC that have been activated by proinflammatory cytokines such as IL-1β and TNF-α; expression is delayed until de novo mRNA and protein synthesis is complete (4-6 hours). L-selectin is constitutively expressed by most leukocytes, as well as EC. It has a central role in normal T-cell recirculation, and is also involved in Mφ recruitment at sites of inflammation[20Tam F.W. Role of selectins in glomerulonephritis.Clin Exp Immunol. 2002; 129: 1-3Crossref PubMed Scopus (0) Google Scholar]. Selectins bind carbohydrate counterligands through an N-terminal C-type lectin domain. The ligands for E- and P-selectin, which are constitutively expressed on Mφ, are closely related to sialyl Lewis X (sLeX) and sialyl Lewis A (sLeA). L-selectin can also bind these ligands and sulphated polysaccharides such as GlyCAM-1, MadCAM-1, and heparan sulfate proteoglycans (HSPGs) on EC and ECM[19Brady H.R. Leukocyte adhesion molecules and kidney diseases.Kidney Int. 1994; 45: 1285-1300Abstract Full Text PDF PubMed Google Scholar]. Integrins are heterodimeric receptors that are constitutively expressed on Mφ. They are activated by conformational changes triggered following ligation of receptors on rolling Mφ by molecules (including chemokines) sequestered at the EC surface (see below). The cell then firmly adheres to the EC through interactions between the β1 integrin, very late activation antigen-4 (VLA-4), and the β2 integrin, leukocyte functional antigen-1 (LFA-1), and their respective counter-receptors vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). These are constitutively expressed by ECs at low levels, and heavily up-regulated by proinflammatory cytokines such as IL-1β, interferon-γ (IFN-γ), and TNF-α[19Brady H.R. Leukocyte adhesion molecules and kidney diseases.Kidney Int. 1994; 45: 1285-1300Abstract Full Text PDF PubMed Google Scholar]. Following firm adherence to EC, Mφ elongate through extension of lamellipodium to form leading edge adhesive complexes that provide traction. The cells then crawl along gradients of chemotactic factors and adhesion molecules to intercellular junctions, where there is diapedesis to the subendothelial space. VLA-4 preferentially mediates lateral migration along the endothelium to the intercellular junction; LFA-1 primarily mediates diapedesis[21Weber C. Springer T.A. Interaction of very late antigen-4 with VCAM-1 supports transendothelial chemotaxis of monocytes by facilitating lateral migration.J Immunol. 1998; 161: 6825-6834PubMed Google Scholar]. The first stages of diapedesis are directed by homophilic interactions of platelet-endothelial-cell adhesion molecule-1 (PECAM-1), expressed on the luminal side of EC and intercellular junctions. Deeper penetration of Mφ through the clefts between EC is then promoted by CD99. Both PECAM-1 and CD99 are constitutively expressed; this is in contrast with junctional adhesion molecule-1 (JAM-1), a ligand for LFA-1. In quiescent EC, JAM-1 is exclusively localized to tight junctional complexes and involved in permeability control. On cell activation, JAM-1 is relocated to the apical aspect of ECs with a resultant alteration in tight junction structure and increased permeability to leukocytes (reviewed in[22Aurrand-Lions M. Johnson-Leger C. Imhof B.A. The last molecular fortress in leukocyte trans-endothelial migration.Nat Immunol. 2002; 3: 116-118Crossref PubMed Scopus (38) Google Scholar]). Subsequent passage through the basal lamina is dependent on contact between ECM and Mφ expressed PECAM-1[23Muller W.A. Randolph G.J. Migration of leukocytes across endothelium and beyond: Molecules involved in the transmigration and fate of monocytes.J Leukoc Biol. 1999; 66: 698-704Crossref PubMed Scopus (164) Google Scholar]. Further interactions between VLA-4 and VLA-5 and underlying matrix then facilitate tissue migration along a bioactive gradient[24Weber C. Alon R. Moser B. Springer T.A. Sequential regulation of alpha 4 beta 1 and alpha 5 beta 1 integrin avidity by CC chemokines in monocytes: Implications for transendothelial chemotaxis.J Cell Biol. 1996; 134: 1063-1073Crossref PubMed Google Scholar]. While the processes at this stage are less well characterized than those that promote transendothelial migration, chemokines sequestered on ECM at an increasing concentration toward inflammatory areas have a central role. Chemokines are small chemotactic cytokines that direct leukocyte recruitment in inflammation and homeostasis through ligation of chemokine receptors expressed on the surface of leukocytes. To date, over 40 chemokines and 19 chemokine receptors have been identified. Chemokines are classified by a nomenclature (CX3CL, CXCL, CCL, and CL) that describes the relative positions of the first 2 conserved cysteine (C) residues of the molecule to any other residue (X) in the 4 cysteine motif common to all chemokines. This is reviewed in detail elsewhere[25Murphy P.M. Baggiolini M. Charo I.F. et al.International union of pharmacology. XXII. Nomenclature for chemokine receptors.Pharmacol Rev. 2000; 52: 145-176PubMed Google Scholar]. For chemokine receptors, the nomenclature used reflects the class of ligating chemokines: that is, CX3CR, CXCR, CCR, and CR. Many chemokines can bind to several different receptors within a subclass, and receptors may bind several different chemokines. However, differential chemokine expression at inflammatory sites and differential lineage and activation-dependent receptor expression by leukocyte subsets confers specificity in recruitment to tissue sites. Stimuli for the expression of inducible chemokines are diverse and include proinflammatory cytokines (e.g., TNF-α, IL-1β, IFN-γ), immune complexes, complement activation products, and nonimmune stimuli such as shear stress. Chemokines presented to circulating Mφ may be produced by EC or originate locally from other sources; for example, extravascular chemokines may be internalized at the abluminal surface of ECs and transcytozed for luminal presentation. The rolling of Mφ on EC selectins may allow exposure to inflammatory chemokines whose modes of presentation and differential receptor targeting may initiate disparate effects. For example, growth-related oncogene-α (GRO-α/CXCL1) is immobilized on the EC surface by HSPGs; it ligates CXCR2 to rapidly convert rolling to firm adhesion by activating Mφ integrins. Conversely, monocyte chemoattractant protein-1 (MCP-1/CCL2) is expressed unbound in a soluble form; through CCR2, it mediates Mφ shape change, spreading, and subsequent transendothelial migration[26Weber K.S. von Hundelshausen P. Clark-Lewis I. et al.Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow.Eur J Immunol. 1999; 29: 700-712Crossref PubMed Scopus (164) Google Scholar]. Some chemokines may act both on adhesion and chemotaxis; for example, regulated upon activation, normal T cell expressed and secreted (RANTES/CCL5) is presented by EC proteoglycans, and acts through CCR1 to promote integrin-mediated firm adhesion. This chemokine can then support Mφ spreading and shape change primarily through CCR5. Subsequent transendothelial migration in response to soluble RANTES/CCL5 is then directed by both CCR1 and CCR5[27Weber C. Weber K.S. Klier C. et al.Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)1-like/CD45RO(+) T cells.Blood. 2001; 97: 1144-1146Crossref PubMed Scopus (157) Google Scholar]. MCP-1/CCL2 and RANTES/CCL5 differentially and selectively regulate the avidity of Mφ expressed integrins. They induce early activation and deactivation of VLA-4 to facilitate transendothelial diapedesis, and late and persistent VLA-5 activation to mediate subsequent interactions with matrix proteins in the basement membrane and ECM[24Weber C. Alon R. Moser B. Springer T.A. Sequential regulation of alpha 4 beta 1 and alpha 5 beta 1 integrin avidity by CC chemokines in monocytes: Implications for transendothelial chemotaxis.J Cell Biol. 1996; 134: 1063-1073Crossref PubMed Google Scholar]. Following migration to the subendothelial space, movement along a chemokine gradient may be facilitated by expression of matrix degradative enzymes by Mφ. Both MCP-1/CCL2 and RANTES/CCL5 are capable of inducing this production, further amplifying the potential for recruitment of subsequent waves of leukocytes to inflammatory sites[28Robinson S.C. Scott K.A. Balkwill F.R. Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-alpha.Eur J Immunol. 2002; 32: 404-412Crossref PubMed Scopus (121) Google Scholar]. P-selectin and E-selectin are present on peritubular and glomerular capillaries in patients with glomerulonephritis of various causes, but not detectable in the tubulointerstitium or glomeruli of renal tissue obtained from normal human kidneys[20Tam F.W. Role of selectins in glomerulonephritis.Clin Exp Immunol. 2002; 129: 1-3Crossref PubMed Scopus (0) Google Scholar]. The level of expression in disease correlates with the extent of the interstitial inflammatory infiltrate and degree of tubular atrophy and scar formation. L-selectin expression by interstitial cells has been demonstrated in disease, and correlates with the infiltration of Mφ[20Tam F.W. Role of selectins in glomerulonephritis.Clin Exp Immunol. 2002; 129: 1-3Crossref PubMed Scopus (0) Google Scholar]. Ligands for L-selectin, including sLex, are found at the corticomedullary junction in human glomerulonephritides, and expression relates to interstitial leukocyte infiltration[29Takaeda M. Yokoyama H. Segawa-Takaeda C. et al.High endothelial venule-like vessels in the interstitial lesions of human glomerulonephritis.Am J Nephrol. 2002; 22: 48-57Crossref PubMed Scopus (10) Google Scholar]. The corticomedullary junction is also a preferential site of P- and E-selectin expression[20Tam F.W. Role of selectins in glomerulonephritis.Clin Exp Immunol. 2002; 129: 1-3Crossref PubMed Scopus (0) Google Scholar]. There is low-level expression of ICAM-1 by peritubular capillaries in normal kidney. This expression is heavily increased in disease states, with increased vascular expression and de novo expression by tubular epithelial cells; this correlates with inflammatory cell infiltration and the extent of tubulointerstitial injury. Infiltrating interstitial cells also express ICAM-1 and its counterligand, LFA-1[19Brady H.R. Leukocyte adhesion molecules and kidney diseases.Kidney Int. 1994; 45: 1285-1300Abstract Full Text PDF PubMed Google Scholar]. VCAM-1 is expressed at low levels on peritubular capillaries and tubular epithelium in normal kidneys. In disease, this expression is increased at both sites and correlates with the extent of tubulointerstitial damage and VLA-4 expression on infiltrating leukocytes[19Brady H.R. Leukocyte adhesion molecules and kidney diseases.Kidney Int. 1994; 45: 1285-1300Abstract Full Text PDF PubMed Google Scholar]. A number of chemokines have been identified in secondary TI disease (reviewed in[30Anders H.J. Vielhauer V. Schlondorff D. Chemokines and chemokine receptors are involved in the resolution or progression of renal disease.Kidney Int. 2003; 63: 401-415Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar]). The expression of chemokines active against Mφ is listed inTable 3. The majority of studies have focused on MCP-1/CCL2 and RANTES/CCL5. Abbreviations are: TEC, tubular epithelial cell; MNC, mononuclear cell; PTC, peritubular capillary; MIP, macrophage inflammatory protein. This chemokine is expressed by tubular epithelial cells (TEC), infiltrating monocytes, and peritubular capillary endothelial cells in a number of renal diseases. Expression in situ, and in the urine of patients with chronic progressive renal disease, correlates with interstitial macrophage infiltration and fibrosis[31Cockwell P. Howie A.J. Adu D. Savage C.O. In situ analysis of C-C chemokine mRNA in human glomerulonephritis.Kidney Int. 1998; 54: 827-836Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 32Grandaliano G. Gesualdo L. Ranieri E. et al.Monocyte chemotactic peptide-1 expression in acute and chronic human nephritides: A pathogenetic role in interstitial monocytes recruitment.J Am Soc Nephrol. 1996; 7: 906-913PubMed Google Scholar, 33Prodjosudjadi W. Gerritsma J.S. van Es L.A. et al.Monocyte chemoattractant protein-1 in normal and diseased human kidneys: An immunohistochemical analysis.Clin Nephrol. 1995; 44: 148-155PubMed Google Scholar, 34Mezzano S.A. Droguett M.A. Burgos M.E. et al.Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy.Kidney Int. 2000; 57: 147-158Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 35Wada T. Furuichi K. Segawa-Takaeda C. et al.MIP-1alpha and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis.Kidney Int. 1999; 56: 995-1003Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 36Wada T. Furuichi K. Sakai N. et al.Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy.Kidney Int. 2000; 58: 1492-1499Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 37Rovin B.H. Doe N. Tan L.C. Monocyte chemoattractant protein-1 levels in patients with glomerular disease.Am J Kidney Dis. 1996; 27: 640-646Abstract Full Text PDF PubMed Google Scholar]. Urinary MCP-1/CCL2 is probably primarily derived from tubulointerstitial sources in these nonproliferative diseases, as glomerular tuft expression is not detected (personal observation;Figure 3e and f)" @default.
• W1999944709 created "2016-06-24" @default.
• W1999944709 creator A5002036920 @default.
• W1999944709 creator A5031282432 @default.
• W1999944709 date "2005-08-01" @default.
• W1999944709 modified "2023-10-18" @default.
• W1999944709 title "Macrophages and progressive tubulointerstitial disease" @default.
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