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
| Introduction|| |
A recent article by Karkar highlighted the relation between cytokines and glomerulonephritis.  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 ,, 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. 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|| |
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. 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.  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.,
Professor Detlef Schlondorff of Munich has done outstanding work in this field., 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. 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|| |
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. The genes for cytokines and chemokines are activated by NFkB. In a recent study of glomerulosclerosis in ageing mice,  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, 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, like the myofibroblasts, there is ERK activation. 
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?|| |
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.  Certain growth factors like PDGF-D are really good at attracting macrophages  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.  So, macrophages will assemble in the renal interstitium. Hypoxia up regulates release of VEGF by macrophages  and so even more macrophages congregate.
| Chemokine Receptors: Designed to be Upsetting|| |
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  Only CCR2 for MCP-1α is evident in human diabetic nephropathy. CCRl is critical for interstitial macrophage and T cell recruitment in lupus nephritis. 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.  In biopsies from patients with IgA nephropathy, CCR2 and CXCR3 are prominent. CCRl and CCR5 are both expressed on macrophages and T lymphocytes but regulate different stages of the leukocyte-endothelial cell interaction 
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.  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  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 , 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  are based on mouse experiments but the prospect will be clarified.
How the chemokines regulate differentiation of T cells is pertinent to our subject.  MCP-l (CCL2) helps the formation of Th2 lymphocytes with CCR3, CCR4 and CCR5 phenotype. 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|| |
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. Meanwhile, hopes are pinned on possible manipulation of the chemokines. 
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. 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, and their associated Th2 cytokines like IL-13, which induce fibrosis.  This latter article lists means of thwarting fibrosis.
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E Nigel Wardle
37 Princess Road, Camden, London NW1 8JS
[Table - 1], [Table - 2]