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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2006  |  Volume : 17  |  Issue : 1  |  Page : 5-9
Chemokines and Glomerulonephritis


37 Princess Road, Camden, London NW1 8JS, United Kingdom

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Keywords: Chemokines, Growth Factors, Macrophages, Glomerulonephritis, Glomerulo-sclerosis, Tubulointerstitial Fibrosis.

How to cite this article:
Wardle E N. Chemokines and Glomerulonephritis. Saudi J Kidney Dis Transpl 2006;17:5-9

How to cite this URL:
Wardle E N. Chemokines and Glomerulonephritis. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2020 Jun 3];17:5-9. Available from: http://www.sjkdt.org/text.asp?2006/17/1/5/32437

   Introduction Top


A recent article by Karkar highlighted the relation between cytokines and glomerulo­nephritis. [1] It seems appropriate to tackle the contribution of chemokines to glomerulo­nephritis as well as tubulointerstitial fibrosis of the kidneys. A classification of the cytokines, chemokines and growth factors will help. They can be abbreviated using the alphabets, CGHIKLM: C, Chemokines; G, Growth Factors; H, Haemopoietic Growth Factors; I, Interferons IFNα , IFNβ, IFNγ ; K (killing) Tumour Necrosis Factors; L, (lymphokine) interleukins; M, Macrophage Activating Factors (MAFs).

Chemokines are mediators that attract immune cells. The chemokines that promote inflammation in tissues are many, and we now have a complex nomenclature for them [2],[3],[4] and for their receptors. The G-X-C chemo­kines tend to attract neutrophils and the C-C chemokines attract monocyte-macrophages.

Consider for a moment the recent finding that the growth factor PDGF, together with vascular endothelial growth factor (VEGF), have been shown to be major participants in the pathogenesis of finger clubbing.[5] VEGF is commonly driven by hypoxia 6 to cause the vascularization of ischemic tissues. Thus, it is angiogenic and we see the results of its action at the back of the eyes in diabetic retinopathies.


   Chemokines and Progressive Kidney Disease Top


We now appreciate that when glomeruli are damaged by inflammation, [l] growth factors are filtered into the urine where they activate renal tubular cells thereby causing them to secrete chemokines and cytokines.[7] These mediators are secreted through the baso­lateral sides of the tubular cells, so that they will exert their main action in the interstitium of the renal medulla, PDGF from tubular cells and TGF-β , derived from medullary macrophages, which causes proliferation of fibroblasts. [7] An accumulation of interstitial white cells, consisting mainly of lymphocytes and macrophages, precedes fibroblast proliferation, their differentiation into myo­fibroblasts, and formation of extra cellular matrix including new collagen.[8],[9]

Professor Detlef Schlondorff of Munich has done outstanding work in this field.[8],[9] He has demonstrated how mutual stimulation between infiltrating leukocytes (attracted by chemokines) and fibroblasts gives rise to glomerulosclerosis and progressive tubular damage and hence, renal fibrosis. Behind all this is the activity of chemokines and their receptors.[10] Schlondorff has described (a) an initiation phase when injury to renal tubular cells induces leukocyte infiltration, (b) an amplification phase when infiltrating leukocytes enhance local production of cytokines and chemokines, (c) a progre­ssion phase when macrophages in the glomeruli stimulate mesangial cells to secrete fibronectin and collagen type IV and when there are interstitial infiltrates, and (d) a terminal phase of glomerulosclerosis, extensive tubular atrophy and diffuse kidney scarring and shrinkage.


   Cell Signalling Top


Today, in the literature, one will find articles embellished with details of cell­signal transduction. In order to achieve increased formation of cytokines and chemokines by (mesangial) cells, there has to be nuclear factor-kappa B activation.[11] The genes for cytokines and chemokines are activated by NFkB. In a recent study of glomerulosclerosis in ageing mice, [12] it was deduced that increased serum TNFα might contribute to increased Rantes expression by their mesangial cells, so explaining recruitment of macrophages. Macrophage mediated renal injury depends on JNK path­way signaling,[13] as judged by the effect of the inhibitor SP600125. In fact, there is activation of MAP kinases in infiltrating inflammatory cells like macrophages, and in proliferating glomerular endothelial or renal tubular cells. In cells that will promote fibrosis,[14] like the myofibroblasts, there is ERK activation. [15]

The obsessive interest in cell-signaling stems from the fact that inhibitors can be devised to thwart signaling pathways. However, the problem will be to confine their actions to the kidneys.


   How do Macrophages become involved? Top


Clearly, damage to the glomerular basement membranes by antibodies or, the deposition of immune complexes in the glomerular filters will lead to the attraction of macrophages. [1] Certain growth factors like PDGF-D are really good at attracting macro­phages [16] and so are chemokines like MCP-1 (CCL2) and Rantes (CCL5). They arise from endothelial cells, from mesangial cells and from fibroblasts. Endothelin is chemotactic for monocyte-macrophages and so is VEGF.

Professor Leon Fine suggested that hypoxia in the renal medulla helps subsequent fibrosis. We know now that when cells are short of oxygen, the transcription factor HIF­la is stabilized and this regulates at least 30 genes, such as those for PDGF and VEGF. [17] So, macrophages will assemble in the renal interstitium. Hypoxia up regulates release of VEGF by macrophages [18] and so even more macrophages congregate.


   Chemokine Receptors: Designed to be Upsetting Top


In crescentic GN, there is expression of CCRl for MCP-3, CCR2 for MCP-1, CCR5 for MlP-la and CXCR3 for IP-10, Mig and I-Tac [19] Only CCR2 for MCP-1α is evident in human diabetic nephropathy.[19] CCRl is critical for interstitial macrophage and T cell recruitment in lupus nephritis.[20] By using unilateral ureteric obstruction, it was shown that CCRl (for ligands CCL3 and CCL4) is relevant to progressive renal fibrosis. CCRl deficient mice had reduced renal TGFβ , reduced numbers of interstitial fibroblasts and reduced formation of collagen type I. [21] In biopsies from patients with IgA nephropathy, CCR2 and CXCR3 are prominent.[19] CCRl and CCR5 are both expressed on macrophages and T lympho­cytes but regulate different stages of the leukocyte-endothelial cell interaction [22]

CXCR3 and CCR5 are expressed on activated T cells. Indeed, CXCR3 is typical of Th-1 lymphocytes. In biopsies, CXCR3 is localized to interstitial T cells, but it is not seen in glomeruli. [23] Thus, CXCR3 could be pertinent to progressive loss of kidney function.

CR4 (for SDF-l, stromal cell derived factor) is up regulated by hypoxia via HIF-lα [24] which suggests that it could be relevant in hypoxic zones like the renal medulla. Indeed, SDF-1 is recognized to support hemopoietic stem cells (HSCs). SDFl will attract monocyte­macrophages and lymphocytes, and intere­stingly it supports dendritic cells.Yes, there are dendritic cells in the kidneys!

Those interested in immunology will know that there is vast literature on how chemo­kines enable the various inflammatory cells to attract each other in order to mount innate and then adaptive immunity to a microbial invader [25],[26] Thus, macrophages exposed to lipopolysaccharide or peptide­glycan release IL-8 (CXCL8), which helps to attract neutrophils, while Rantes and MIPl-α/β attract dendritic cells. Unfortu­nately, the details [27] are based on mouse experiments but the prospect will be clarified.

How the chemokines regulate differen­tiation of T cells is pertinent to our subject. [28] MCP-l (CCL2) helps the formation of Th2 lymphocytes with CCR3, CCR4 and CCR5 phenotype.[28] CCL3 (MIPlα), CCL4 (MIPlβ)), CCL5 (Rantes) act on T cells with CCR5 receptors (for MIP1β) ) to enable formation of interleukin 12 and hence Thl cells which form IFNγ.


   The End is Fibrosis Top


There are some clever ways of reducing glomerular and tubulointerstitial inflam­mation and subsequent fibrosis, such as the use of hepatocyte growth factor (HGF), which, is an inhibitor of NFkB.[29] Mean­while, hopes are pinned on possible manipulation of the chemokines. [19]

How TGFβ and its ally CTGF (connective tissue growth factor) cause fibrosis is a topic for another day. They promote tubular epithelial cells to myofibroblast transition.[30] Meanwhile, we have to note that there are several types of macrophages: Ml macrophages are the typical aggressive macrophages that cause cellular immunity and tissue damage. In doing so, they form the MAF IFNγ, which happens to oppose fibrosis. These Ml macrophages produce iNOS (NOS2). There are also M2 repair macrophages that produce arginase,[31] and their associated Th2 cytokines like IL-13, which induce fibrosis. [32] This latter article lists means of thwarting fibrosis.[32]

 
   References Top

1.Karkar A. Cytokines and glomerulonephritis. Saudi J Kidney Dis Transplant.2004; 15(4):473-85.  Back to cited text no. 1    
2.Furie MB, Randolph G J. Chemokines and tissue injury. Am J Pathol.1995;146:1287-301.  Back to cited text no. 2    
3.Murdoch C, Finn A. Chemokine receptors and their role in inflammation and infectious diseases.Blood 2000;95:3032-43.  Back to cited text no. 3    
4.Zlotnik A, Yoshie O. Chemokines:a new classification system and their role in immunity.Immunity 2000; 12:121-7.  Back to cited text no. 4    
5.Atkinson S, Fox SB. Vascular endothelial growth factor (VEGE)-A and platelet­derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing. J Pathol 2004;203:721-8.  Back to cited text no. 5    
6.Cross MJ, Dixelius J, Matsumoto T, Chesson­Welsh L. Vascular endothelial growth factor­receptor signal transduction Trend Biochem Sci.2003;28:488-94.  Back to cited text no. 6    
7.Hirschberg R, Wang S. Proteinuria and growth factors in the development of tubulointerstitial injury and searing in kidney disease.Curr Op in Nephrol Hypertens 2005;14(l):43-52.  Back to cited text no. 7    
8.Anders HJ, Vielhauer V, Schlondorff D. Chemokines and chemokine receptors are involved in the resolution or progression of renal disease.Kidney Int 2003;63:401-15.  Back to cited text no. 8    
9.Segerer S, Nelson PJ, Schlondorff D. Chemokines,chemokine receptors and renal disease: from basic science to pathophy­siologic and therapeutic studies. J Am Soc Nephrol 2000;11:152-76.  Back to cited text no. 9    
10.Murphy PM, Baggiolini M, Chan IF, et al. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmcol Rev 2000;52:145-76.  Back to cited text no. 10    
11.Wardle EN. Nuclear factor kappa-B for the nephrologist.Nephrol Dial Transplant.2001; 16:1764-8.  Back to cited text no. 11    
12.Zheng F, Cheng QL, Plati AR, et al. The glomerulosclerosis of aging in females contribution of the proinflammatory mesangial cell phenotype to macrophage infiltration .Am J Pathol 2004; 165:1789-98.  Back to cited text no. 12    
13.Ikezumi Y, Hurst L, Atkins RC, Nikolic­Paterson DJ. Macrophage mediated renal injury is dependent on signalling via the JNK pathway. J Am Soc Nephrol 2004;15:1775-84.  Back to cited text no. 13    
14.Park SJ, Jeong KS. Cell type specific activation of mitogen activated protein kinases in PAN-induced progressive renal disease in rats. Biochem Biophys Res Commun 2004;323(l):l-8.  Back to cited text no. 14    
15.Masaki T, Stambe C, Hill PA, et al .Activation of the extracellular signal related protein kinase pathway in human glomerulopathies. J Am Soc Nephrol 2004;15:1835-43.  Back to cited text no. 15    
16.Uutala M, Wirzenius M, Paavonen K, et al. PDGF-D induces macrophage recruit­ment,increased interstitial pressure and blood vessel maturation during angio-genesis.Blood 2004;104:3198-204.  Back to cited text no. 16    
17.Maxwell P. HIF-l: an oxygen response system with special relevance to the kidney. J Am Soc Nephrol 2003;14:2712-22.  Back to cited text no. 17    
18.Burke B, Giannoudis A, Corke KP, et al. Hypoxia induced gene expression in human macrophages implications for ischemic tissues and hypoxia regulated gene therapy.Am J Pathol 2003;163:1233-43.  Back to cited text no. 18    
19.Anders HJ, Vielhauer V, Schlondorff D. Current paradigms about chemokines as therapeutic targets. Nephrol Dial Transplant 2004;19:2948-64.  Back to cited text no. 19    
20.Anders HJ, Belemezova E, Eis V, et al. Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr)mice. J Am Soc Nephrol 2004; 15:1504-13.  Back to cited text no. 20    
21.Eis V, Luckow B, Vielhauer V, et al. Chemokine receptor CCR1 but not CCR5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction. Am Soc Nephrol 2004; 15:337-47.  Back to cited text no. 21    
22.Weber C, Weber KS, Klier C, et al. Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H).l-like/CD45RO(+) T cells. Blood 2001;97:1144-6.  Back to cited text no. 22    
23.Segerer S, Banas B, Wornle M, et al. CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis. Am J Pathol 2004; 164:635-49.  Back to cited text no. 23    
24.Schioppa T, Uranchimeg B, Saccano A, et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 2003;1 98:1391-402.  Back to cited text no. 24    
25.Luster A D. The role of chemokines in linking innate and adaptive immunity. Curr Opin Immunol2002;14:129-35.  Back to cited text no. 25    
26.Delves P J, Roitt I M. The Immune System. N Engl J Med 2000;343:3-49 and 108-17.  Back to cited text no. 26    
27.Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol 2000; 18:217-42.  Back to cited text no. 27    
28.Luther S A, Cyster J G. Chemokines as regulators of cell differentiation. Nat Immunol 2001;2:102-7.  Back to cited text no. 28    
29.Gong R Rifai A, Tolbert E M, et al. Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remnant kidney by modulating tubular expression of macrophage chemoattractant protein-1 and R. J Am Soc Nephrol 2004; 15:2868-81.  Back to cited text no. 29    
30.Zhang C,Meng X,Zhu Z,Liu J,Deng A.Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro. Cell Biol Int 2004;28(12):863-73.  Back to cited text no. 30    
31.Gordon M. Alternative activation of macro­phages.Nat Rev Immunol 2003;3:23-35.  Back to cited text no. 31    
32.Wynn T A. Fibrotic disease and the T(H)l/T(H)2 paradigm. Nat Rev Immunal 2004;4:583-94.  Back to cited text no. 32    

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Correspondence Address:
E Nigel Wardle
37 Princess Road, Camden, London NW1 8JS
United Kingdom
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    Introduction
    Chemokines and P...
    Cell Signalling
    How do Macrophag...
    Chemokine Recept...
    The End is Fibrosis
    References
    Article Tables
 

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