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NDT Advance Access published online on April 2, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn129
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Understanding renal disorders as systemic diseases: the fascinating world of basement membranes beyond the glomerulus*

Oliver Gross

Department of Nephrology and Rheumatology, University of Göttingen, Göttingen, Germany

Correspondence and offprint requests to: Oliver Gross, Department of Nephrology and Rheumatology, University Hospital Göttingen, Robert-Koch Str. 40, D-37075 Göttingen, Germany. Tel: +49-551-39-6331; Fax: +49-551-39-8906; E-mail: gross.oliver{at}med.uni-goettingen.de

Keywords: Alport syndrome; chronic renal fibrosis; extracellular matrix; glomerular basement membrane; type IV collagen

In the 27 December 2007 issue of the New England Journal of Medicine, Plaisier and colleagues [1] describe fascinating data on a new spectrum of autosomal dominant hereditary collagen diseases involving the COL4A1 gene. This gene codes for the {alpha}1-chain of type IV collagen, being the most important structural component of all basement membranes throughout the body. The paper was highly publicized and completes a trilogy of manuscripts about collagen type IV {alpha}1-chain mutations causing neonatal porencephaly, adult stroke, perinatal cerebral haemorrhage, skin lesions and nephropathies [1–3].

All basement membranes consist of a network of type IV collagen. Collagen IV monomers contain a long triple helical rod built by >1000 Gly-X-Y repeats, which is terminated at its C-terminal end by a globular NC1 domain, well known to nephrologists due to Goodpasture syndrome (Figure 1). In contrast to {alpha}-chains of the fibre forming collagens (types I, II, III and V), collagen IV chains contain interruptions in their Gly-X-Y repeats. These interruptions endow the collagen IV triple helix with a high degree of flexibility compared to fibre-forming collagens. Six genetically distinct {alpha}-chains of type IV collagen have been identified, forming a network of {alpha}1{alpha}1{alpha}2(IV), {alpha}3{alpha}4{alpha}5(IV) and {alpha}5{alpha}5{alpha}6(IV) [4]. Whereas the {alpha}1{alpha}1{alpha}2(IV) trimers are widely expressed in all basement membranes throughout the body, the {alpha}3{alpha}4{alpha}5(IV) network localizes to the glomerular basement membrane, lung, eye and lens and the {alpha}5{alpha}5{alpha}6(IV) network to Bowman's capsule and the oesophagus [5].


Figure 1
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  		Fig. 1 Predicted interaction between the matrix and cells via tissue-specific type IV collagen receptors. Intact triple-helix formation of type IV collagen due to glycine-X-Y-repeats seems to be crucial for intact matrix signalling. The red tail on the left represents a glycine-missense mutation described by Plaisier et al. [1]. The altered folding of the {alpha}1{alpha}1{alpha}2(IV) triple-helix results in an abnormal receptor signalling via type IV collagen receptors such as discoidin domain receptors 1 and 2 (DDR1 and 2) [10] or {alpha}1β1- and {alpha}2β1-integrins [11]. Cell signalling beyond type IV collagen receptors is still a black box. Within the glomerulus, this black box includes connective tissue growth factor (CTGF) and TGFβ leading to chronic renal fibrosis and failure. The black box can be positively influenced by ACE inhibition; this might be a very important part of the their nephroprotective properties [12].

 
Alport syndrome is derived from a mutation of either the COL4A3, COL4A4 or COL4A5 gene, coding for {alpha}3, {alpha}4 or {alpha}5 chain of type IV collagen, i.e. collagen types that constitute basement membranes in the renal glomerulus, the ear and the eye. In knockout mice and humans mutations in COL4A1 have recently been associated with cerebral haemorrhage and porencephaly, a rare autosomal dominant condition characterized by cystic brain cavities and cerebral white-matter lesions [2,3]. Data from COL4A1 knockout mice models extend our view on collagen IV mutations as a systemic disease by describing endoplasmic reticulum and intracellular stress [6] leading to defects of the eye and vascular stability, the brain and kidney function and postnatal viability [7]. The present study by Plaisier et al. [1] completes this type IV collagen story by describing a systemic syndrome involving not only the brain but also all basement membranes including small vessels and large arteries as well as the skin and the kidney. This report opens a fascinating world beyond the well-known basement membrane of the glomerulus.

But do we really know much about the basement membrane? We know it is there and is needed to give cells some orientation, and serves as a part of a filter in the glomerulus. We have known that for over 20 years [8]. But we still do not know much about what the basement membrane proteins really do in the extracellular matrix, how they interact with whom and by which. This might explain why COL4A1 mutations involve a confusing number of different organs. By focussing on a well-known basement membrane disease of the glomerulus, Alport syndrome, nephrologists might explain some of the confusing findings in COL4A1 mutations.

(a) Can nephrologists’ knowledge about the glomerular basement membrane explain the clinical manifestations of COL4A1 mutations?
COL4A1 mutations lead to a severe systemic disease; how can we explain the very different phenotypes (angiopathy, nephropathy, aneurysms and muscle cramps) described? Goodpasture syndrome is limited to the lung and kidney; Alport syndrome is limited to the glomerular basement membrane, the inner ear and lens. Mutations involving the {alpha}5- and {alpha}6-chain of type IV collagen result in Alport syndrome plus leiomyomatosis of the oesophagus. Therefore, as nephrologists we know about the tissue-specific contribution of different type IV collagen chains. This knowledge even helps us to understand why COL4A1 mutations affect all parts of the body, but not the mature glomerular basement membrane or Bowman's capsule [{alpha}5{alpha}5{alpha}6(IV)-chains], and only the tubular basement membrane within the kidney [1]. How can we explain angiopathies and aneurysms? Again, the kidney might help us if we concentrate on the vascular basement membrane. Similar to the glomerulus, the small vessels in the brain are very vulnerable with an outstanding effect: haemorrhagy and stroke. Weakening and disorganization of these small vessels by a COL4A1-missense mutation will do harm sooner or later as seen in the brain and eyes of affected family members [1]. The muscle cramps are explained by transient ischaemia and microhaemorrhages as well as disorganization of the muscular basement membrane resulting in abnormal muscle function.

(b) Can nephrologists’ knowledge about the glomerular basement membrane predict the phenotype–genotype correlation in COL4A1-mutations?
All human families with COL4A1 mutations have missense mutations in exons 24 or 25 leading to substitution of glycine to another amino acid. Is this just a coincidence? No, we know from Alport syndrome that glycine-X-Y-missense mutations are most common (~40%) and lead to a relatively benign phenotype depending on their distance from the NC1-domain [9]. As COL4A1 mutations lead to a more systemic disease, one can expect mutations with a larger impact on protein function to be lethal. These data were confirmed in COL4A1 knockout mice [2,3]. Only smaller impacts on protein integrity such as missense mutations could lead to a (mis-)functioning mis-folded protein that can still be incorporated in the basement membrane. This mutated protein is likely to be degraded faster. In conclusion, only embryos with a milder missense COL4A1 mutation can survive organogenesis. Only newborns with a mildly altered protein, which still can be incorporated within the basement membrane, can survive their basement membrane defects for a certain time. Similar to Alport syndrome focussing on glomerular (vascular) damage, the phenotype of COL4A1 mutations focuses on areas with the most mechanical stress, such as the vessels.

(c) If nephrologists understand the glomerular matrix, will we understand the fascinating world beyond?
Despite knowing most of the different matrix components for >20 years [8], we can only speculate about their function by investigating their malfunction in type IV collagen diseases such as Alport syndrome. One key point might be the cell–matrix interaction via type IV collagen receptors. These receptors are tyrosinekinase receptors binding collagens at the cell surface, passing signals through the plasma membrane to the nucleus. By this they regulate cell proliferation, cell transformation, cell migration, ageing of cells as well as apoptosis [14] in almost every single cell of our organism such as epithelial, mesenchymal, endothelial cells, fibroblasts, haemapoetic cells, etc. We know that these receptors influence implantation of blastocytes and maturation of mammalian glands. We know that collagen can activate macrophages via collagen receptors through a p38-MAPK- and NF-{kappa}B-dependent upregulation of IL-8, macrophage inflammatory protein-1{alpha} and monocyte chemoattractant protein-1 [15]. Chronic fibrosis can be delayed in mice lacking the DDR1-collagen receptor [16]. We have recently started to understand how the matrix and its receptors influence tumour angiogenesis and metastasis [17]. The complex mechanisms of tumour invasion beyond the matrix barrier and the tissue-specific growth of metastasis are closely linked to type IV collagen and its receptors.

For many of us being nephrologists the glomerulus might be the centre of the world. If we understand more about the matrix holding this small glomerular world together, will we learn about functions of the basement membrane beyond?

Oh yes, we can. We certainly can learn a lot about the fascinating basics of embyrogenesis, organogenesis, acute and chronic organ damage and healing, chronic fibrosis, tumour invasion and metastasis and how to treat and cure numerous chronic diseases. We have now started to accept that the matrix is not a virtually unorganized, dead mass lying under cells.



   Acknowledgments
 
This editorial comment on the extracellular matrix and its receptors is in memory of my friend Wolfgang F. Vogel, a young excellent and enthusiastic researcher in this field, who passed away recently.

Conflict of interest statement. None declared.



   Notes
 
* Comment on Plaisier E, Gribouval O, Alamowitch S et al. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle, cramps. N Engl J Med 357:2687–2695 Back

1 Comment on [1] Back



   References
Top
 References
 

  1. Plaisier E, Gribouval O, Alamowitch S, et al. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med (2007) 357:2687–2695.[Abstract/Free Full Text]
  2. Gould D, Phalan FC, Breedveld G, et al. Mutations in COL4A1 cause perinatal cerebral hemorrhage and porencephaly. Science (2005) 308:1167–1170.[Abstract/Free Full Text]
  3. Gould D, Phalan FC, van Mil S, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med (2006) 354:1489–1496.[Abstract/Free Full Text]
  4. Hudson BG, Tryggvason K, Sundaramoorthy M, et al. Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med (2003) 348:2543–2556.[Free Full Text]
  5. Miner JH. Building the glomerulus: a matricentric view. J Am Soc Nephrol (2005) 16:857–861.[Free Full Text]
  6. Favor J, Gloeckner CJ, Janik D, et al. Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, mus musculus: an extension of the COL4A1 allelic series and the identification of the first two COL4A2 mutant alleles. Genetics (2007) 175:725–736.[Abstract/Free Full Text]
  7. Gould DB, Marchant JK, Savinova OV, et al. COL4A1 mutation causes endoplasmatic reticulum stress and genetically modifiable ocular dysgenesis. Hum Mol Genet (2007) 16:798–807.[Abstract/Free Full Text]
  8. Timpl R. Recent advances in the biochemistry of glomerular basement membrane. Kidney Int (1986) 30:293–298.[Web of Science][Medline]
  9. Gross O, Netzer K-O, Lambrecht R, et al. Meta-analysis of genotype–phenotype correlation in X-linked Alport syndrome: impact on genetic counseling. Nephrol Dial Transplant (2002) 17:1218–1227.[Abstract/Free Full Text]
  10. Gross O, Beirowski B, Addicks K, et al. DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria. Kidney Int (2004) 66:102–111.[CrossRef][Web of Science][Medline]
  11. Cosgrove D, Rodgers K, Meehan D, et al. Integrin alpa1beta1 and transforming growth factor-β1 play distinct roles in Alport glomerular pathogenesis and serve as dual targets for metabolic therapy. Am J Pathol (2000) 157:1649–1659.[Abstract/Free Full Text]
  12. Gross O, Beirowski B, Koepke M-L, et al. Pre-emptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int (2003) 63:438–446.[CrossRef][Web of Science][Medline]
  13. Greenberg SM. Small vessels, big problems. N Engl J Med (2006) 354:1451–1453.[Free Full Text]
  14. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature (2001) 411:355–365.[CrossRef][Medline]
  15. Matsuyama W, Wang L, Farrar WL, et al. Activation of discoidin domain receptor 1 isoform b with collagen up-regulates chemokine production in human macrophages: role of p38 mitogen-activated protein kinase and NF-{kappa}B. J Immunol (2004) 172:2332–2340.[Abstract/Free Full Text]
  16. Avivi-Green C, Singal M, Vogel WF. Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis. Am J Respir Crit Care Med (2006) 174:420–427.[Abstract/Free Full Text]
  17. Vogel WF, Abdulhussein R, Ford CE. Sensing extracellular matrix: an update on discoidin domain receptor function. Cell Signal (2006) 18:1108–1116.[CrossRef][Web of Science][Medline]
Received for publication: 13. 2.08
Accepted in revised form: 18. 2.08


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