Role of extracellular matrix components in renal pathophysiology
Liliana Schaefer (group leader), Kristin Moreth, Jinyang Zeng-Brouwers, Madalina Nastase, Helena Frey, Nimitha Rose Mathew, Riad Haceni
IIn recent years it has become increasingly clear that extracellular matrices (ECMs) are far more than merely structural scaffolds that help to organize cells into tissues by providing mechanical support. Instead, ECMs are highly dynamic macromolecular assemblies that exert profound influences on cell behaviour. This is due to both, receptor-dependent interactions of cells with resident components of the ECM (such as collagens, laminins, and fibronectin) as well as to cell signaling by transiently bound mediators (growth factors, cytokines, and chemokines). Interaction of these mediators with ECM components has been recognized to profoundly impact on their biological properties, such as activity, availability to receptors, etc.
Our group is particularly interested in the contribution of the ECM to normal renal physiology and to its role in kidney disease. Chronic kidney diseases are an important issue as they eventually develop into terminal kidney insufficiency, requiring replacement therapies such as dialysis and transplantation. In Germany alone, 12.000 new cases of end-stage renal failure are reported every year. Common hallmark of chronic kidney disease is progressive fibrosis of the kidney, presenting morphologically either as glomerulosclerosis or as tubulo-interstitial fibrosis. In both circumstances, initial injury to the kidney leads to activation of resident cells that, by secretion of soluble mediators (growth factors, cytokines, and chemokines), mediate apoptosis, proliferation, epithelial-mesenchymal transdifferentiation, and inflammatory cell infiltration. Mechanisms primarily intending to repair tissue damage then progressively lead to accumulation of ECM, due both to increased synthesis and decreased degradation of matrix components.
The ultimate aim of our research is the elucidation of cellular and molecular mechanisms leading to inflammation and fibrosis of the kidney, in order to find new targets for anti-inflammatory and anti-fibrotic therapies.
Our current work focusses on the role(s) of the TGF-beta-binding, small leucine-rich repeat proteoglycans decorin and biglycan in the development of renal fibrosis. We could demonstrate that both molecules, though employing different mechanisms, impact on proliferation, differentiation, apoptosis, adhesion, and migration of kidney cells. Importantly, both proteoglycans are by themselves signaling molecules. While decorin activates Akt/PKB and p21WAF1/CIP1 via binding to the IGF-I receptor, thus inhibiting apoptosis of endothelial and tubular epithelial cells, biglycan inhibits adhesion and proliferation of mesangial cells. We could further demonstrate that biglycan, upon release from either the ECM or from macrophages, is capable to boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2. These results provide evidence for a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor.
Prof. Liliana Schaefer is an Associated Editor of The Journal of Histochemistry & Cytochemistry (http://jhc.sagepub.com/). She is on the Editorial Board of the Journal of Biological Chemistry, and presides over the German Connective Tissue Society (http://www.dgbf.de/).
Key references:
1. Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhão JG, Lemarchand P, Pfeilschifter J, Schaefer RM, Iozzo RV, Schaefer L: Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and miR-21. Sci Signal. 4, ra75, 2011
Paper available at : http://www.pzf.de/allg/publications/publications2011.php
Editors’ choice: Science 334:1033, 2011
Research Highlight: Nat Immunol 13:19, 2012
2. Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk S, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, , Rittinger K, Macek B, Dikic I: SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471: 637-641, 2011
3. Moreth K, Brodbeck R, Babelova A, Gretz N, Spieker T, Zeng-Brouwers J, Pfeilschifter J, Young M, Schaefer RM, Schaefer L: The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis. J Clin Invest 120: 4251-72, 2010
Highlight: Nature Reviews Immunology 11, 6-7 (January 2011) | doi:10.1038/nri2911
4. Babelova A, Moreth K, Tsalastra-Greul W, Zeng-Brouwers J, Eickelberg O, Young MF, Bruckner P, Pfeilschifter J, Schaefer RM, Gröne H-J, Schaefer L: Biglycan: a danger signal that activates the NLRP3 inflammasome via a Toll-like- and P2X-multireceptor complex. J Biol Chem 284:24035-24048, 2009
5. Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Gotte M, Malle E, Schaefer RM, Grone HJ: The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest 115:2223-2233, 2005
