Abstract
Progressive renal disease is characterized by expansion of the tubulo-interstitium and accumulation of extracellular matrix within this tissue compartment. Interstitial fibroblasts are the primary producers of the interstitial matrix, and in the evolution of tubulo-interstitial fibrosis these cells undergo changes, namely increased proliferation, differentiation to myofibroblasts, and altered extracellular matrix metabolism, all of which, in other cell types, have been shown to be regulated by the major family of extracellular matrix receptors, the integrins. In the normal kidney, interstitial fibroblasts express α1, α4, α5, and β1 integrins, and fibrosis is associated with increased expression of α1, α2, α5, αv, and β1 integrins. In particular, α5, β1, and αv are suggested to be linked with the fibrotic process. In vitro, renal fibroblasts express a similar range of integrins, and ligation of selected receptors is associated with specific functions. Ligation of α6 stimulates proliferation, while α5 promotes expression of myofibroblastic phenotype, and β1 integrin has been implicated in cell contraction. Recent studies suggest that renal fibroblasts also express the non-integrin matrix receptors, discoidin domain receptors, and that changes in activation of these receptors may be associated with fibrogenic events. Thus the current, albeit limited, data suggest an important role for receptors for extracellular matrix molecules in the pathogenesis of progressive renal fibrosis.
References
1.
Hynes RO: Integrins: Versatility, modulation and signaling in cell adhesion. Cell 1992;69:11–25.
2.
Akiyama SK: Integrins in cell adhesion and signaling. Hum Cell 1996;9:181–186.
3.
Clark EA, Brugge JS: Integrins and signal transduction pathways: The road taken. Science 1996;268:233–239.
4.
Giancotti FG: Integrin signaling: Specificity and control of cell survival and cell cycle progression. Curr Opin Cell Biol 1997;9:691–700.
5.
Meredith JE, Winitz S, McArthur Lewis J, Hess S, Ren X-D, Renshaw MW, Schwartz MA: The regulation of growth and intracellular signaling by integrins. Endocr Rev 1996;17:207–220.
6.
Yamada KM: Integrin signaling. Matrix Biol 1997;16:137–141.
7.
Juliano RL, Haskill S: Signal transduction from the extracellular matrix. J Cell Biol 1993;120:577–580.
8.
Brooks PC, Klemke RL, Schön S, Lewis JM; Schwartz MA, Cheresh DA: Insulin-like growth factor receptor cooperates with integrin αvβ5 to promote tumor cell dissemination in vivo. J Clin Invest 1997;99:1390–1398.
9.
Woodard AS, Garcia-Cardena G, Leong M, Madri JA, Sessa WC, Languino LR: The synergistic activity of αvβ3 integrin and PDGF receptor increases cell migration. J Cell Sci 1998;111:469–478.
10.
Lichtner RB, Howlett AR, Lerch M, Xuan JA, Brink J, Langton-Webster B, Schneider MR: Negative cooperativity between alpha3beta1 and alpha2beta1 integrins in human mammary carcinoma MDA MB231 cells. Exp Cell Res 1998;240:368–376.
11.
Higgins JM, Mandlebrot DA, Shaw SK, Russell GJ, Murphy EA, Chen YT, Nelson WJ, Parker CM, Brenner MB: Direct interaction of integrin alpha E beta7 with E-cadherin. J Cell Biol 1998;141:197–210.
12.
Kadmon G, Altevogt P: The cell adhesion molecule L1: Species- and cell-type-dependent multiple binding mechanisms. Differentiation 1997;61:143–150.
13.
Huttenlocjer A, Lokonishok M, Kinder M, Wu S, Truong T, Knudsen KA, Horwitz AF: Integrin and cadherin synergy regulate inhibition of migration and motile activity. J Cell Biol 1998;141:515–526.
14.
Ignotz RA, Massague J: Cell adhesion protein receptors are targets for transforming growth factor-β. Cell 1987;51:189–195.
15.
Pickering JG, Uniyal S, Ford CM, Chau T, Laurin MA, Chow LH, Ellis CG, Fish J, Chan BM: Fibroblast growth factor-2 potentiates vascular smooth muscle cell migration to platelet-derived growth factor: Upregulation of integrin and disassembly of actin filaments. Circ Res 1997;80:627–637.
16.
Xu J, Clark RAF: Extracellular matrix alters PDGF regulation of fibroblast integrins. J Cell Biol 1996;132:239–249.
17.
Ashkenas J, Damsky CH, Bissell MJ, Werb Z: Integrins: Signaling and the remodeling of the extracellular matrix; in Cheresh DA, Mecham RP (eds): Integrins: Molecular and Biological Responses to the Extracellular Matrix. San Diego, Academic Press, 1994, pp 79–109.
18.
Paller M: Integrins and repair after acute renal injury. Kidney Int 1997;52(suppl 61):52–55.
19.
Lieberthal W, McKenny JB, Keifer CR, Snyder LM, Kroshian VM, Sjaastad MD: Beta-1-integrin-mediated adhesion between renal tubular cells after anoxic injury. J Am Soc Nephrol 1997;8:175–183.
20.
Romanov V, Noiri E, Czerwinski G, Finsinger D, Kesser H, Goligorsky MS: Two novel probes reveal tubular and vascular Arg-Gly-Asp (RGD) binding sites in the ischemic rat kidney. Kidney Int 1997;52:93–102.
21.
Hillis GS, Roy-Chaudhury P, Duthie LA, Stewart KN, Brown PA, Simpson JG, MacLeod AM: Expression of β1 integrins in IgA nephropathy. Nephrol Dial Transplant 1997;12:1137–1142.
22.
Roy-Chaudhury P, Hillis G, McDonald S, Simpson JG, Power DA: Importance of the tubulointerstitium in human glomerulonephritis. II. Distribution of integrin chains β1, α1 to 6 and αV. Kidney Int 1997;52:103–110.
23.
Roy-Chaudhury P, Wu B, King G, Campbell M, MacLeod AM, Haites N, Simpson JG, Power DA: Adhesion molecule interactions in human glomerulonephritis: Importance of the tubulointerstitium. Kidney Int 1996;49:127–134.
24.
Jin DK, Fish AJ, Wayner EA, Mauer M, Setty S, Tsilibary E, Kim Y: Distribution of integrin subunits in human diabetic kidneys. J Am Soc Nephrol 1996;7:2636–2645.
25.
Tang WW, Feng L, Xia Y, Wilson CB: Extracellular matrix accumulation in immune mediated tubulointerstitial injury. Kidney Int 1994;45:1077–1084.
26.
Eddy A: Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 1996;7:2495–2508.
27.
Kaissling B, Hegyi I, Loffing J, Le Hir M: Morphology of interstitial cells in the healthy kidney. Anat Embryol 1996;193:303–318.
28.
Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG: Identification and characterisation of a fibroblast marker: FSP1. J Cell Biol 1995;130:393–405.
29.
Saalbach A, Aust G, Haustein UF, Herrman K, Anderegg U: The fibroblast-specific Mab AS02: A novel tool for detection and elimination of human fibroblasts. Cell Tissue Res 1997;290:593–599.
30.
Bosseloir A, Heinen E, Defrance T, Bouzhazha F, Antione N, Simar LJ: Moabs MAS516 and 5B5, two fibroblast markers, recognise human follicular dendritic cells. Immunol Lett 1994;42:49–54.
31.
El Nahas M: Renal scarring: A multi-organ approach to fibrosis. Exp Nephrol 1995;3:65–148.
32.
Schmitt-Graff A, Desmoulière A, Gabbiani G: Heterogeneity of myofibroblast phenotypic features: An example of fibroblastic cell plasticity. Virchows Arch 1994;425:3–24.
33.
Groma V: Demonstration of collagen type VI and alpha-smooth muscle actin in renal fibrotic injury in man. Nephrol Dial Transplant 1998;13:305–312.
34.
Hägg PM, Hägg PO, Peltonen S, Autio- Harmainen H, Pihlajaniemi T: Location of type XV collagen in human tissues and its accumulation in the interstitial matrix of the fibrotic kidney. Am J Pathol 1997;150:2075–2086.
35.
Romberger DJ: Fibronectin. Int J Biochem Cell Biol 1997;29:939–943.
36.
Taipale J, Keski-Oja J: Growth factors in the extracellular matrix. FASEB J 1997;11:51–59.
37.
Johnson RJ: Cytokines, growth factors and renal injury: Where do we go from here? Kidney Int 1997;52(suppl 63):2–6.
38.
Couchman JR, Woods A: Syndecans: Signaling and cell adhesion. J Cell Biochem 1996;61:578–584.
39.
Alvarez RJ, Sun MJ, Haverty TP, Iozzo RV, Mayers JC, Neilson EG: Biosynthetic and proliferative characteristics of tubulointerstitial fibroblasts probed with paracrine cytokines. Kidney Int 1992;41:14–23.
40.
Lewis M, Fine LG, Norman JT: Pexicrine effects of basement membrane components on paracrine signalling by renal tubular cells. Kidney Int 1996;49:48–58.
41.
Rodemann HP; Müller G, Knecht A, Norman JT, Fine LG: Fibroblasts of the rabbit kidney in culture. I. Characterization of growth properties and identification of cell-specific markers. Am J Physiol 1991;261:F283–F291.
42.
Müller GA, Frank J, Rodemann HP, Engler-Blum G: Human renal fibroblast cell lines (tFKIF and tNKF) are new tools to investigate pathophysiologic mechanisms of renal interstitial fibrosis. Exp Nephrol 1995;3:127–133.
43.
Norman JT, Clark IM, Garcia PL: Hypoxia co-ordinately regulates extracellular matrix production and turnover to promote fibrogenesis in human renal fibroblasts: An oxygen-responsive system independent of autocrine mediators. Kidney Int, submitted 1999.
44.
Johnson DW, Saunders HJ, Baxter RC, Field MJ, Pollock CA: Paracrine stimulation of human renal fibroblasts by proximal tubular cells. Kidney Int 1998;54:747–757.
45.
Ivarsson M, McWhirter A, Black CM, Rubin C: Impaired regulation of collagen proα1(I) mRNA and change in pattern of collagen binding integrins on scleroderma fibroblasts. J Invest Dermatol 1993;101:216–221.
46.
Kirk TZ, Mark ME, Chua CC, Chua BH, Mayes MD: Myofibroblasts from scleroderma skin synthesise elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem 1995;270:3423–3428.
47.
Magor G, Fraggetta F, Travali S, Lanzafame S: Immunohistochemical expression and distribution of alpha2beta1, alpha6beta1, alpha5beta1 integrins and their extracellular ligands type IV collagen, laminin and fibronectin in palmar fibromatosis. Gen Diag Pathol 1997;143:203–208.
48.
Jin DK, Kim Y, Mauer M, Fioretto P, Vats A, Fish AJ: Relationships of cell proliferation and expression of integrin subunits and type I collagen in skin fibroblasts with renal lesions in patients with IDDM. Am J Kidney Dis 1998;31:293–300.
49.
Orphanides C, Norman JT: Hypoxia alters integrin expression in human proximal tubular epithelial cells (PTE) and cortical interstitial fibroblasts (CF). J Am Soc Nephrol 1997;8:523.
50.
Rodemann HP, Müller GA: Characterisation of human renal fibroblasts in health and disease. II. In vitro growth, differentiation and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am J Kidney Dis 1991;17:684–686.
51.
Norman JT, Goligorsky M: Ligation of integrins (I) dictates the phenotype of rat kidney fibroblasts (NRK-49F). J Am Soc Nephrol 1997;8:523.
52.
Desmoulière A, Darby I, Costa AM, Raccurt M, Tuchweber B, Sommer P, Gabbiani G: Extracellular matrix deposition, lysyl oxidase expression and myofibroblastic differentiation during the initial stages of cholestatic fibrosis in the rat. Lab Invest 1997;76:765–778.
53.
Rønnov-Jessen L, Petersen OW: A function for filamentous α-smooth muscle actin: Retardation of motility in fibroblasts. J Cell Biol 1996;134:76–80.
54.
Kelynack K, Hewitson T, Pedagogos E, Nicholls K, Becker G: Renal myofibroblasts contract solidified collagen matrix. J Am Soc Nephrol 1997;8:519.
55.
Kuhara T, Kagami S, Kuroda Y: Expression of β1 integrins on activated mesangial cells in human glomerulonephritis. J Am Soc Nephrol 1997;8:1679–1687.
56.
Bissell DM: Hepatic fibrosis and wound repair: A progress report. J Gastroenterol 1998;33:295–302.
57.
Gotwals PJ, Chi-Rosso G, Lindner V, Yang J, Ling L, Fawell SE, Koteliansky VE: The α1β1 integrin is expressed during neointima formation in rat arteries and mediates collagen matrix reorganisation. J Clin Invest 1996;97:2469–2477.
58.
Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G: The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta 1. J Cell Biol 1998;142:873–881.
59.
Norman JT, Lewis MP, Fine LG, Orphanides C: The role of extracellular matrix (ECM) and growth factors in the activation of renal fibroblasts. J Am Soc Nephrol 1995;6:905.
60.
Desmoulière A, Redard M, Darby I, Gabbiani G: Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995;146:56–66.
61.
Brooks P: Role of integrins in angiogenesis. Eur J Cancer 1996;32:2423–2429.
62.
Bunn HF, Poynton R: Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 1996;76:839–885.
63.
Suzuma K, Takagi H, Otani A, Honda Y: Hypoxia and vascular endothelial growth factor stimulate angiogenic integrin expression in bovine microvascular endothelial cells. J Invest Ophthalmol Vis Sci 1998;39:1028–1035.
64.
Yao CC, Breuss J, Pytela R, Kramer RH: Functional expression of the α7 integrin receptor in differentiated smooth muscle cells. J Cell Sci 1997;110:1477–1487.
65.
Schnapp LM, Breua JM, Ramos DM, Sheppard D, Pytela R: Sequence and tissue distribution of the human integrin alpha 8 subunit: A beta 1 associated alpha subunit expressed in smooth muscle cells. J Cell Sci 1995;108:537–544.
66.
Desmoulière A, Badid C, Bochaton-Piallat ML, Gabbiani G: Apoptosis during wound healing, fibrocontractive diseases and vascular wall injury. Int J Biochem Cell Biol 1997;29:19–30.
67.
Malik RK: Regulation of apoptosis by integrin receptors. J Pediatr Hematol Oncol 1997;19:541–545.
68.
Rozzo C, Chiesa V, Caridi G, Pagnan G, Ponzoni M: Induction of apoptosis in human neuroblastoma cells by abrogation of integrin-mediated cell adhesion. Int J Cancer 1997;70:688–698.
69.
Brooks PC, Montgomery AMP, Rosenfled M, Reisfeld RA, Hu T, Klier G, Cheresh DA: Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994;79:1157–1164.
70.
Vassalli J-D, Sappino A-P, Belin D: The plasminogen activator/plasmin system. J Clin Invest 1991;88:1067–1072.
71.
Birkedal-Hansen H, Moore WGI, Bodden MK, Windsor LJ, Birkedal-Hansen B, De Carlo A, Engler JA: Matrix metalloproteinases: A review. Crit Rev Oral Biol Med 1993;4:197–250.
72.
Stetler-Stevenson WG: Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix. Am J Pathol 1996;148:1345–1350.
73.
Denhardt DT, Feng B, Edwards DR, Cocuzzi ET, Malyankar UM: Tissue inhibitors of metalloproteinases (TIMP, aka ERP): Structure, control of expression and biological functions. Pharmacol Ther 1993;59:329–341.
74.
Gomez DE, Alonso DF, Yoshiji H, Thorgiesson UP: Tissue inhibitors of metalloproteinases: Structure, regulation and biological functions. Eur J Cell Biol 1997;74:111–122.
75.
Riikonen T, Westermarck J, Koivisto L, Borberg A, Kähäri V-M, Heino J: Integrin α1β1 is a positive regulator of collagenase (MMP-1) and collagen α1(I) gene expression. J Biol Chem 1995;270:13548–13552.
76.
Xue W, Mizumaki I, Rodd RF, Petty HR: Urokinase plasminogen activator receptors associate with beta1 and beta3 integrins of fibrosarcoma cells: Dependence on extracellular matrix components. Cancer Res 1997;57:1682–1689.
77.
Preissner KT, May AE, Wohn KD, Germer M, Kanse SM: Molecular cross talk between adhesion receptors and proteolytic cascades in vascular remodelling. Thromb Haemost 1997;78:88–95.
78.
Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Ainmes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA: Localisation of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin αvβ3. Cell 1996;85:683–693.
79.
Mercier I, Lechaire JP, Desmoulière A, Gaill F, Aumailley M: Interactions of human skin fibroblasts with monomeric or fibrillar collagens induce different organisation of the cytoskeleton. Exp Cell Res 1996;225:245–266.
80.
Sudbeck BD, Parks WC, Welgus HG, Pentland AP: Induction and repression of collagenase by keratinocytes is controlled by distinct components of different extracellular matrix components. J Biol Chem 1997;272:22103–22110.
81.
Langholz O, Rockel D, Mauch C, Kozlowska E, Bank I, Kreig T: Collagen and collagenase gene expression in three-dimensional collagen lattices are differentially regulated by α1β1 and α2β1 integrins. J Cell Biol 1995;131:1903–1915.
82.
Xie B, Laouar A, Huberman E: Fibronectin-mediated cell adhesion is required for induction of 92-kDa type IV collagenase/gelatinase (MMP-9) gene expression during macrophage differentiation. J Biol Chem 1998;273:11576–11582.
83.
Huhtala P, Humphries MJ, McCarthy JB, Tremble PM, Werb Z: Cooperative signaling by α5β1 and α4β1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin. J Cell Biol 1995;129:867–879.
84.
Kjoller L, Kanse SM, Kirkergaard T, Rodenburg KW, Ronne E, Goodman SL, Preissner KT, Ossowski L, Andreasen PA: Plasminogen activator inhibitor-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res 1997;232:420–429.
85.
Schwarting A, Schlaak J, Lotz J, Pfers I, Meyer-zum Buschenfelde KH, Mayet WJ: Endothelin modulates the expression of adhesion molecules on fibroblast-like synovial cells. Scand J Rheumatol 1996;25:246–256.
86.
Farrell DH, Al-Mondhiry HA: Human fibroblast adhesion to fibrinogen. Biochemistry 1997;36:1123–1128.
87.
Svee K, White J, Vaillant P, Jessurun J, Roongta U, Krumwiede M, Johnson D, Henke C: Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44. Am J Respir Crit Care Med 1996;154:1819–1828.
88.
Ricardo SD, Levinson ME, De Joseph MR, Diamond JR: Expression of adhesion molecules in rat renal cortex during experimental hydronephrosis. Kidney Int 1996;50:202–210.
89.
Harning R, Pelletier J, Lubbe K, Takei F, Merluzzi VJ: Monoclonal antibody to MALA-2 (ICAM-1) reduces autoimmune nephritis in kd/kd mice. Clin Immunol Immunopathol 1992;64:129–134.
90.
Vogel W, Gish GD, Alves F, Pawson T: The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997;1:13–23.
91.
Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, Davies S, Goldfarb MP, Glass DJ, Lernke G, Yancopoulos GD: An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell 1997;1:25–34.
92.
Roth T, Podesta F, Stepp MA, Boeri D, Lorenzi M: Integrin overexpression induced by high glucose and by human diabetes: Potential pathway to cell dysfunction in diabetic microangiopathy. Proc Natl Acad Sci USA 1993;90:9640–9644.
93.
Krishnamurti U, Rondeau E, Sraer JD, Michael AF, Tsilibary EC: Alterations in human glomerular epithelial cells interacting with nonenzymatically glycosylated matrix. J Biol Chem 1997;272:27966–27970.
94.
Norman J, Brought C, Romanov V, Goligorsky M: Glycation of the extracellular matrix (ECM) alters rat renal fibroblast (NRK-49F) growth, differentiation and ECM production. J Am Soc Nephrol 1998;9:638A.
1999
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
