THE ROLE OF SYNDECAN-1 IN KIDNEY REGENERATION
Madelein Seppenwoolde s1852817 9 juli 2012
Mentor: Jaap van den Born, Nephrology UMCG
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INDEX
ABSTRACT ... 3
1. INTRODUCTION ... 4
2. INSTRINSIC REGENERATION ... 5
General intrinsic regenerative capacity ... 5
Intrinsic regenerative capacity of the kidney ... 6
3. PROTEOGLYCANS... 8
4. SYNDECAN-1 ... 9
Co-receptor ... 10
Functions in diseases ... 10
Functions in wound healing in general ... 11
Function in wound healing in the kidney ... 11
Regulation of syndecan-1 expression ... 12
Shedding ... 12
5. DISCUSSION ... 14
REFERENCES ... 16
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ABSTRACT
Losing kidney function is dangerous and lead to chronic renal failure. In chronic renal failure there is interstitial fibrosis (IF) and many nephrons are destroyed by tubular atrophy (TA). An ideal solution for chronic renal failure would be slowing down the disease and stimulating kidney regeneration. Kidney regeneration can be executed by kidney stem cells, bone marrow stem cells and intrinsic (epithelial) kidney cells of which the last seem to be the most important.
Recent investigations showed that proteoglycans (PGs) might influence the regenerative process of the kidney. This thesis focuses on syndecan-1 which is a cell surface trans membrane PG of the heparan sulfate proteoglycans (HSPGs) family. In adult tissues, syndecan-1 is predominantly expressed by both simple and stratified epithelial cells and plasma cells. Sydecan-1 carry out its functions by serving as a co-receptor for many different receptors. Investigations showed that syndecan-1 (via the heparan sulfate side chains) might be capable of protecting and regenerating the damaged cells and therefore inducing tubule repair after injury. Syndecan-1 expression is induced by TGF- β and EGF and reduced by TNF-α and IL-1β. Syndecan-1 can also be shed from the cell surface by MMP-7, MMP-9, MMP-14 and ADAM17, resulting in soluble syndecan-1 (sSynd-1). Shedding can rapidly reduce the syndecan-1 expression on the cell surface which leads to less responsive cells. sSynd-1 can function in an autocrine or paracrine manner by binding growth factors and cytokines and then binding to the corresponding receptor. sSynd-1 may inhibit cell proliferation during wound repair and therefore can inhibit epithelial wound healing. To stimulate regeneration after injury syndecan-1 expression should be stimulated and shedding should be avoided. Syndecan-1 can be stimulated by all-trans retinoic acid (ATRA) or n-3 polyunsaturated fatty acids (n-3 PUFA) diet. Shedding can be avoided by the antioxidant enzyme extracellular superoxide dismutase (EC-SOD) or by the tissue inhibitor of metalloproteinase-3 (TIMP3). Syndecan-1 can be a novel therapeutic target in treatment of chronic renal failure.
Keywords: Kidney regeneration, Syndecan-1, co-receptor, shedding
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1. INTRODUCTION
The kidney is an essential organ in our body. If the kidney isn’t functioning well people can get seriously ill and eventually die (Nierstichting, 2012).
The most important function of the kidney is the filtration of the blood. Besides that the kidney also regulates the water, acid-base and electrolyte balance. The kidney also regulates several endocrine processes by secreting hormones which influence the blood pressure (via renine), the vitamin D metabolism (via calcitriol) and the production of red blood cells (via erythropoietin).
The kidney is a horseshoe shaped organ which exists of two layers: the cortex and the medulla.
Every kidney is composed of 1 to 2 million nephrons. The glomerulus is located at the beginning of the nephron. The glomerulus is a little structure where the blood is pressed through the wall of the capillaries. The filtrate goes into Bowman’s space and then flows through a system of renal tubules prior to result in the collection tube, which emits the formed urine in the renal pelvis. In the tubules reabsorption and secretion occurs so that homeostasis of water, acid-base and electrolyte balance is ensured (Silverthorn, 2010).
As mentioned before losing kidney function is dangerous and lead to chronic renal failure. In chronic renal failure there is almost always interstitial fibrosis (IF) and many nephrons are destroyed by tubular atrophy (TA). This combination of histopathological symptoms is usually abbreviated to by the term IFTA (Eddy, 2005).
These symptoms can have different causes. There are congenital and acquired disorders (Nierstichting, 2012) which can cause this kidney damage including diabetes and also the inability to repair the kidney after acute kidney injury (AKI)(Palevsky, 2012).
IF in the kidney is caused by recruiting of inflammatory leukocytes and myofibroblasts to the renal intersititium. Circulating monocytes are also recruited because of chemo attractant molecules and leukocyte adhesion molecules. Then the macrophages secrete molecules (eg transforming growth factor β) which stimulate the fibroblasts and epithelial cells to become myofibroblasts. The myofibroblasts produce exaggerated amounts of extracellular matrix (ECM) which causes fibrosis. Because of the fibrosis many components of the kidney are destroyed, which also causes TA (Eddy, 2005).
When a patient is diagnosed with chronic kidney failure it is tried to preserve residual renal function by medication and diet. Often these methods cannot save the kidneys and the patient needs other treatment. There are two possible treatments from which the patient may benefit:
dialysis and renal transplantation. With dialysis only the filter function and the regulation of the internal environment can be regulated. The hormonal function of the kidney cannot be regulated and because of this the regulation of the blood pressure, the production of red blood cells and the amount of calcium in the bones (due to the Vitamin D) are still a problem. Dialysis can adopt 8-10 % of the renal function. This is enough to keep the patient alive. There are also other disadvantages: the patient can only take a limited amount of liquid and has to stick to a strict diet (Nierstichting, 2012).
To be eligible for a kidney transplant the patient needs a good overall health. The transplanted kidney is in most cases placed in the lower abdomen and can be derived from a deceased or living donor. To get a kidney from a deceased donor the patient has to be on the waiting list for
>4 years. Because of this long waiting time, in the Netherlands, nowadays 50% of the transplanted kidneys are from living donors. The living donors are often a relative of the patient.
5 A living donor is able to donate one of the kidneys because a single kidney alone is sufficient for a good renal function. After transplantation a patient has to take immunosuppressive medication to avoid rejection of the kidney. This medication has many side effects, such as increased risk of infections and nephrotoxicity, but after transplantation it is again possible to have a reasonable normal live (Nierstichting, 2012).
Kidney transplantation and dialyses both have many disadvantages so a better solution for chronic kidney failure would be desirable. An ideal solution for chronic kidney failure could be slowing down the disease and stimulating kidney regeneration. This might reduce IFTA and maintenance of the renal function. This thesis will be about kidney regeneration. For this purpose we first looked at the intrinsic regeneration of different organs and thereafter kidney regeneration is explained in more detail. Finally, the possible role of syndecan-1 in renal regeneration is discussed to see if it offers starting points to new therapies.
2. INSTRINSIC REGENERATION
General intrinsic regenerative capacity
There are many animals which are able to regenerate organs or parts of their body. One of them is the Axolotl (Ambystoma mexicanum), a kind of Salamander which is originated from Mexico.
The Axolotl is often used as a model for human regeneration. The expectation is that because a lot of biological processes and signaling pathways are really conserved (in tetrapods), humans might also be able to regenerate structures through the same biological processes and signaling pathways. Knowledge about the different biological processes and signaling pathways in the Axolotl might be helpful by gaining knowledge about regeneration in humans. This information might eventually be used to stimulate regeneration in humans (McCusker & Gardiner, 2011).
Organs in the human body are able to regenerate to a limited degree. Some organs are better able to regenerate than others. Most of the knowledge about regeneration in humans is derived from research in mammals, but can probably also be applied to humans.
In the intestines and lungs especially stem cells cause regeneration of the organs. The turnover rate in the intestinal epithelium is very high, so regeneration of the intestinal tissue is very well possible (Podolsky, 1999). The stem cells who make regeneration possible are located in the crypts of the intestine and they can differentiate into all cell types of the intestinal wall (Feil et al., 1989).
In the lungs stem cells are found in many different places. Currently research is being conducted to find out which stem cells regenerate which tissue (Baddour, Sousounis, & Tsonis, 2012).
In the liver and skin the regenerative capacity is caused by differentiated cells (Baddour et al., 2012). The liver is capable of regenerating itself from the cells which where leftover after removal of the tissue, even if 70% of the tissue has been removed. (Higgins & Anderson, 1931).
The skin is also able to regenerate itself. Regeneration of the skin starts with closing the wound by blood platelets, blood cells and matrix after which macrophages, neutrophils, T cells and platelets fill the wound. Eventually re-epithelialization occurs caused by keratinocytes (Baddour et al., 2012).
The heart is in humans one of the least regenerative organs. Some animals however do regenerate their heart. This regeneration is performed by cardiomyocytes (Jopling et al., 2010;
Kikuchi et al., 2010). In mammals proliferation of the cardiomyocytes only takes place in fetal
6 life. After birth the proliferation activity of these cells declines (Porrello et al., 2011). This is why the mammalian heart is susceptible for fibrosis.
Intrinsic regenerative capacity of the kidney
Much research is conducted on the regenerative capacity of the kidney. The primary goals in these studies are finding out which cells are able to regenerate and which mediators regulate this regeneration. Several cell types able to contribute to renal regeneration have been identified: differentiated tubular epithelial cells, kidney stem cells and bone marrow stem cells.
The first type of cells which might be able to regenerate (differentiated tubular epithelial cells) might proliferate after kidney injury to produce similar cells and that they can dedifferentiate and then re-enter the cell cycle. Prove has been found. Because tubular cells are able to express vimentin and pax2 (Witzgall, Brown, Schwarz, & Bonventre, 1994) in post-ischemic conditions.
Vimentin and pax2 are mesenchymemale markers. Other research also showed that restoration of nephrons after ischemia reperfusion injury (I/R injury) is mainly carried out by surviving tubular epithelial cells (Humphreys et al., 2008). After renal injury the tubular epithelial cells start to proliferate because they are stimulated by different growth factors, adhesion molecules and cell cycle regulators. The growth factors which are up regulated after renal injury are epidermal growth factor (EGF), heparin binding epidermal growth factor-like growth factor (HB- EGF), Transforming growth factor alpha (TGF-α), insulin-like growth factor I (IGF-I) and hepatocyte growth factor (HGF) (Hammerman, 1998; Schena, 1998). Most of them are produced in the kidney and work through autocrine and paracrine processes. HGF works via an endocrine pathway (El Sabbahy & Vaidya, 2011). Binding of these growth factors to specific receptors on the cells stimulates cells to go from the GO phase to the G1 phase of the cell cycle. As a result these cells undergo DNA synthesis and subsequent mitosis allowing proliferation of the cells (El Sabbahy & Vaidya, 2011).
The Wingless (Wnt) signaling pathway is also important in regenerative capacity via differentiated tubule epithelial cells. A study of Lin et al. has shown that macrophages in the injured kidney produce Wnt-7b, which is a ligand for the Wnt signaling pathway. Wnt-7b stimulates cells to pass the G2 checkpoint of the cell cycle which leads to less apoptosis. If Wnt- 7b is removed from macrophages, the recovery of the kidney after injury is decreased. So Wnt- 7b has a positive influence on recovery and regeneration after renal injury via the Wnt signaling pathway (Lin et al., 2010).
Another molecule which can activate the Wnt signaling pathway is β-Catenin. β-Catenin is a structural component of the intracellular junction. When metabolic stress occurs, β-Catenin moves to the nucleus of the cell and stimulates the activation of the Wnt signaling pathway and consequently stimulation of proliferation and recovery (El Sabbahy & Vaidya, 2011).
The differentiated tubule epithelial cells can also have an effect on the regenerative capacity of themselves and other epithelial cells. Research showed that the distal tubule epithelial cells are less sensitive to apoptosis than the proximal tubule epithelial cells, especially after ischemic injury. The distal tubule epithelial cells also have an autocrine and paracrine function by releasing inflammatory, repairing and survival cytokines. The proximal tubule epithelial cells do not produce these cytokines, but they do have the receptors. This allows the distal tubule epithelial cells to influence the proximal tubule epithelial cells positively (Gobe & Johnson, 2007).
7 Tubule epithelial cells can also influence kidney regeneration by producing Colony Stimulating factor 1 (CSF-1). In a study where CSF-1 was injected after ischemic renal injury improved tubule pathology and function were found. There was also less renal fibrosis, more tubule proliferation and the apoptosis of tubule epithelial cells was suppressed. CSF-1 can bind to CSF-1 receptors on macrophages and stimulate the regenerative capacity of macrophages. Mechanisms are unknown but are thought to be regulated via macrophage-stimulating protein (MSP) because in vitro MSP stimulates tubule epithelial cell proliferation (Menke et al., 2009). More research to confirm the role of CSF-1 in renal regeneration and to find out the mechanism behind it is needed.
The second type of cells which could be able to regenerate the kidney after renal injury are kidney stem cells. A cell that might qualify as a renal stem cell is the metanephric mesenchyme cell. This cell plays an important role in the embryonic development of the kidney. Capsule of Bowman cells, podocytes and proximal and distal tubule epithelial cells can arise from the metanephric mesenchyme cell (Herzlinger, Koseki, Mikawa, & al- Awqati, 1992).
Investigators have used two methods to search for the kidney stem cell.
They searched for cells with stem cell markers (CD133 and CD24) and they searched for cells which had the functional properties of a stem cell (Benigni, Morigi, & Remuzzi, 2010).
Four possible stem cell niches were found in the adult kidney: the proximal tubules, glomeruli, peritubular capillaries and the papillae. Al these possible niches are shown in figure 1.
The first group of potential kidney stem cells was found in the tubular fraction of a healthy human renal cortex. These cells express CD133 and were in vitro able to become kidney epithelial cells and kidney endothelial cells. It was also confirmed that these cells were originated from the kidney because they also had a Pax2 marker, which is an embryonic kidney marker. When these cells were implanted in SCID mice with glycerol-induced tubulonecrosis they provided an improved recovery. This was probably caused by integrating of the cells into the damaged tubules (Bussolati et al., 2005).
The second group of potential kidney stem cells expressed CD133 and CD24 and were isolated from the Bowman capsule in an adult kidney. These cells were multipotent and could produce podocytes and tubular cells in vitro (Ronconi et al., 2009). In another investigation, performed
Figure 1: Potential niches for kidney precursor or kidney stem cells.
8 by Sagrinati et al., it was proved that the same cells could cause regeneration of tubule structures of the nephron after injection in mice with AKI. The injection also improved morphologic and functional damage of the kidney (Sagrinati et al., 2006).
The third group of potential kidney stem cells was found in the perivascular niche. They expressed precursor markers from pericytes as well as markers from mesenchyme stem cells and were also able to promote tissue recovery (Bruno et al., 2009).
As mentioned before there are two methods of identifying stem cells. They can not only be recognized by stem cell markers, but also by stem cells specific properties. A stem cell specific property is for example that stem cells divide slowly. Slowly dividing cells can be identified because they are Bromodeoxyuridin (BrdU)-retaining (Yan et al., 2007). The fourth group of potential kidney stem cells was found in the interstitial of renal papillae of rats and mice using this method. During recovery after renal ischemic injury the cells entered the cell cycle and moved out of the renal papillae. Like other stem cells these cells spontaneously formed spheres in vitro. And they also expressed mesenchyme and epithelial proteins (Oliver, Maarouf, Cheema, Martens, & Al-Awqati, 2004).
In conclusion kidney stem cells occur at different locations in the kidney. They may play a significant role in recovery after renal injury.
The third type of cells which could be able to regenerate the kidney after renal injury are bone marrow stem cells. Bone marrow stem cells can be differentiated into different types of blood cells, but they can also differentiate into many different cell lines, such as epithelial cells (Wagers
& Weissman, 2004).
Bone marrow-derived epithelial cells appear in small quantities in the kidney after acute renal failure. In a man who had received a female donor kidney 1% of the present tubule cells were Y- chromosome-positive. Non-renal cells may also participate in regeneration of tubules in the kidney after renal injury (Poulsom et al., 2001). Other researchers tried to reproduce this result, but did not succeed (Duffield et al., 2005).
Although kidney stem cells and bone marrow stem cells can contribute to kidney repair, most researchers agree that most recovery capacity of the kidney comes from intrinsic kidney cells, especially from the kidney epithelial cells.
3. PROTEOGLYCANS
Recent investigations showed that proteoglycans (PGs) could also play an important role in the regenerative process of the kidney (Celie et al., 2012; Matsuo, 2008). PGs are molecules which consist of a protein core with long unbranched polysaccharide chains which are called glycosaminoglycans (GAGs). Hyaluronan (HA) is an exception to this, because HA has no protein core (Prydz & Dalen, 2000; Schaefer & Schaefer, 2010).
There is a wide variety of PGs. This is due to various reasons. The first reason is that there are many different protein cores. There are about thirty of them and all of these different protein cores have different biological activities and functions (Iozzo, 1998).
The second reason is that the GAGs are very diverse and not all protein cores bound to the same amount of GAGs. To some of the PGs only one GAG is bound (e.g. decorin) while to others more
9 than hundred GAGs are bound (e.g. aggrecan). The GAGs are very diverse because they can differ in length and the arrangement of sulfated residues. The sulfation pattern differs also among cell types and different conditions (Esko, Kimata, & Lindahl, 2009). A subdivision of the various PGs is often made based on the different GAGs. There are chrondroitin sulfate (CS), dermatan sulfate (DS), kerataan sulfate (KS) , heparin/heparan sulfate (heparin/HS) and non-sulfated GAGs such as hyaluronan (HA) (Schaefer & Schaefer, 2010).
Synthesis of PGs starts by the cells which take up the building blocks for GAG synthesis (monosaccharides and sulphate). After that the sugars and sulphate are activated by the nucleotide comsumption in the cytosol to form UDP-sugars and 3’-phosphoadenosine 5’- phosphosulphate (PAPS). UDP-sugars and PAPS are then translocated into the endoplasmatic reticulum (ER) and Golgi lumens where the linker tetrasaccharide and the fifth saccharide are formed. The fifth saccharides determine whether the GAG becomes a CS, DS, KS or heparin/HS (Prydz & Dalen, 2000).
After synthesis the proteoglycans are transported from the Golgi to their destinations. They are ubiquitously found throughout the ECM, but they are also found on virtually all cell surfaces and in basement membranes of different tissues (Ly, Laremore, & Linhardt, 2010).
The GAG-chains of the proteoglycans are charged negatively and therefore the GAG-chains can attract cations and bind water. One of the functions of PGs derives from this since hydrated GAG gels enable joints and tissues to absorb large pressure changes (Prydz & Dalen, 2000). The sulfated regions of the GAG-chains can also bind to different cytokines and growth factors and therefore play an important role in the control of growth and differentiation by mediating many biological processes including cell-cell and cell-matrix interaction, growth factor sequestration, chemokines and cytokine activation, microbial recognition, tissue morphogenesis during embryonic development and cell migration and proliferation (Capila & Linhardt, 2002;
Cattaruzza & Perris, 2006; Esko & Selleck, 2002; Garner, Yamaguchi, Esko, & Videm, 2008;
Kreuger, Spillmann, Li, & Lindahl, 2006) . Thereby PGs might also bind to mediators involved in tissue regeneration and remodeling.
As mentioned before recent investigation did show that PGs play an important role in regeneration in the kidney after injury (Celie et al., 2012; Matsuo, 2008). The rest of the thesis will focus on syndecan-1 because syndecan-1 is a main PG in the kidney and syndecan-1 also plays an important role in several diseases. It can modulate leukocyte recruitment, cancer cell proliferation and invasion, angiogenesis, microbial attachment and entry, host defense mechanisms and matrix remodeling (Teng, Aquino, & Park, 2012).
4. SYNDECAN-1
Syndecan-1 is a cell surface trans membrane PG of the heparan sulfate proteoglycans (HSPGs) family. It has a type I membrane core protein with GAG chains covalently attached to the extracellular portion of the protein core. Syndecan-1 has a large extracellular (EC) domain, a single trans membrane domain and a short cytoplasmatic domain and they all contribute to the function of syndecan-1 (Zong et al., 2011). The EC domain has been associated with cell adhesion (Beauvais, Ell, McWhorter, & Rapraeger, 2009; Whiteford et al., 2007), the trans membrane domain is essential in the activation of the cytoplasmic domain and downstream signaling
10 (Alexopoulou, Multhaupt, & Couchman, 2007) and the cytoplasmic domain binds cytoskeletal and regulates dynamics of the actin cytoskeleton and membrane trafficking (Zong et al., 2011).
Syndecan-1 was first identified by the Bernfield (Jalkanen, Nguyen, Rapraeger, Kurn, & Bernfield, 1985) and Höök (Kjellen, Pettersson, & Hook, 1981) research groups. They identified a HSPG intercalated in the plasma membrane of mouse mammary gland epithelial cells and rat hepatocytes, respectively. This HSPG was found to expressed predominantly on the basolateral surface of epithelial cells (Hayashi et al., 1987; Rapraeger, Jalkanen, & Bernfield, 1986) bind to ECM components, such as collagens I, III and V (Koda, Rapraeger, & Bernfield, 1985), fibronectin (Saunders & Bernfield, 1988) and thrombospondin (X. Sun, Mosher, & Rapraeger, 1989), and associate with the actin cytoskeleton (Rapraeger et al., 1986). Because these properties indicated that this HSPG is well positioned to function as an anchor that stabilizes the morphology of epithelial sheets by connecting the ECM to the intracellular cytoskeleton, the name ‘syndecan’ (from the Greek syndein, which means to bind together) was given to this HSPG (Teng et al., 2012). In adult tissues, syndecan-1 is predominantly expressed by both simple and stratified epithelial cells, hepatocytes and plasma cells, although it is expressed at a lower level in several other cell types and its expression can be induced in these cells (Teng et al., 2012).
Co-receptor
Syndecan-1 carries out its functions by serving as a co-receptor for many different receptors. It can bind to extracellular proteins and form a signaling complex with a receptor. Additionally, HSPGs immobilize proteins at the cell surface and mediate protein internalization. Thus, ligand binding is followed by various fates. Outcomes seem to depend on whether the ligand is soluble (i.e. growth factor, cytokine) or insoluble (i.e. cell, ECM component, microbe), whether the ligand also interacts with a signaling receptor, and whether the ligand binds to the HS chains on syndecan-1 or to the core protein (Bernfield et al., 1999) .
Binding of syndecan-1 to insoluble ligands, such as cells and ECM components, immobilizes syndecan-1 in the plane of the membrane, enabling syndecan-1 to interact with the actin cytoskeleton and form a variety of cell-cell, cell-matrix, or cell-microbe adhesions. The cell surface syndecan-1 is a co-receptor in most of these interactions, generating a second signal upon formation of the signaling complex (Bernfield et al., 1999).
Binding of syndecan-1 to soluble ligands, such as growth factors and cytokines, modulates their activity and thereby can activate and inhibit cell proliferation, motility and differentiation. In most cases ligand binding to syndecan-1 is not required for ligand-receptor interaction but it can stimulate the signal (Bernfield et al., 1999).
Functions in diseases
Investigation about syndecan-1 in animal models of diseases have provided clear indication that it plays an important role in the development of inflammatory diseases, cancer and infection.
Syndecan-1 is a critical cofactor in the pathogenesis of these diseases as Syndecan-1-deficient mice only show dramatic pathological phenotypes when challenged with disease-causing agents or conditions, and do not show spontaneous pathologies. In general, syndecan-1 attenuates non- infectious inflammatory diseases by inhibiting leukocyte adhesion onto the activated endothelium, reducing the expression and inhibiting the activity of pro-inflammatory factors, confining leukocyte infiltration to specific sites of tissue injury, or by removing sequestered chemokines and facilitating the resolution of inflammation. In contrast, in cancer and infectious
11 diseases, syndecan-1 functions are mostly propathogenic. Syndecan-1 enhances oncogene and growth factor signaling, inhibits cancer cell apoptosis, and promotes angiogenesis. In infectious diseases, syndecan-1 clearly promotes pathogenesis as it mediates the attachment and entry of pathogens into host cells and inhibits host defense mechanisms. The underlying mechanisms that govern the physiological vs. pathological functions of syndecan-1 are not known, but the unique spatiotemporal expression pattern of syndecan-1 likely mediates its prominent functions in many diseases (Teng et al., 2012).
Functions in wound healing in general
The influence of syndecan-1 presence in several diseases are very important, but for our topic of interest (chronic renal failure) especially the wound healing feature of syndecan-1 needs extra attention. Research did also show an important role of syndecan-1 in wound healing. In patients with inflammatory bowel disease (IBD) syndecan-1 expression in areas of inflamed mucosa is reduced. Investigation showed that this reduce is caused by TNF-α and IL-1β, which are inflammatory cytokines that are present in the intestine of an IBD patient. The quality of mucosal ulcer healing is related to the expression of growth factors and their receptors and loss of syndecan-1 expression may reduce ligand-dependent activation of growth factor receptors thus impairing mucosal healing (Day, Mitchell, Knight, & Forbes, 2003).
The role of syndecan-1 in wound healing is also confirmed by investigation by Elenius et al. After incision remarkably increased amounts of syndecan-1 on the cell surfaces of migrating and proliferating epidermal cells adjacent to the wound margins were noted. This suggests that syndecan-1 may have a unique and important role as a cell adhesion and a growth factor-binding molecule during tissue regeneration in mature tissues (K. Elenius et al., 1991).
Function in wound healing in the kidney
There has not been performed much investigation about syndecan-1 and regeneration or wound healing in the kidney. But the investigations that were performed showed that syndecan-1 also plays an important role in wound healing and regeneration after renal injury.
Matsuo investigated in vitro if syndecan-1 influenced the viability of Mardin-Darby canine kidney (MDCK) cells by also using the KIC-synd-1 cell line which expresses syndecan-1. The investigation showed that if the MDCK cells (with no syndecan-1) were treated with oxalate, the viability of these cells significantly decreased. Treatment of the KIC-synd-1 cells with oxalate did not significantly decrease the viability, so the syndecan-1 presence might have blocked apoptosis and repaired the cells. If the KIC-synd-1 cells were pretreated with heparitinase digestion, to remove all heparan sulfate chains from the syndecan-1, and then treated with oxalate, these cells also showed a significant viability decrease. These results show that after damage to the kidney cells, syndecan-1 (via the heparan sulfate side chains) might be capable of protecting and repairing the damaged cells (Matsuo, 2008).
The most convincing experiment about the regenerative function of syndecan-1 in kidneys was performed by Celie et al. They showed that syndecan-1 expression was increased in tubular epithelial cells in renal allograft biopsies compared with control. The increased syndecan-1 expression correlated with low proteinuria and serum creatinine, less interstitial inflammation, less tubular atrophy and prolonged allograft survival. They also showed that knockdown of syndecan-1 in human tubular epithelial cells in vitro reduced cell proliferation. Investigation with syndecan-1-deficient (syn1 -/-) mice showed that syn1 -/- mice had increased initial renal
12 failure and tubular injury after ischemia/reperfusion injury compared with wild-type mice.
Macrophage and myofibroblast numbers, tubular damage, and plasma urea levels were increased and tubular proliferation reduced in the kidneys of syn1 -/- compared with wild-type mice 14 days following injury. These experiments clearly show that syndecan-1 promotes tubular survival and repair in murine ischemia/reperfusion injury (Celie et al., 2012).
Regulation of syndecan-1 expression
As mentioned before syndecan-1 expression is remarkably increased after injury, probably to repair the injured tissue (K. Elenius et al., 1991). It is important to know how this increase is regulated. Proposed regulators of syndecan-1 expression are cytokines which are released in an injured kidney. There are several studies which looked into this.
In the first study the influence of different cytokines on syndecan-1 expression in normal murine mammary gland (NMuMG) epithelial cells was investigated. This investigation showed that only forskolin and three isoforms of TGF-β significantly induced syndecan-1 expression. TNF-α and basic fibroblast growth factor (bFGF) only seem to have little (not significant) effect on syndecan-1 expression. The induction of syndecan-1 was performed by signaling of TGF-β through protein kinase A (PKA) to phosphorylate the syndecan-1 cytoplasmic domain and increases syndecan-1 expression on epithelial cells (Hayashida, Johnston, Goldberger, & Park, 2006).
In the second study the influence of TNF- α en IL-1β on syndecan-1 expression in colonic epithelial cells was investigated. Both the cytokines caused down-regulation of syndecan-1 at protein and mRNA levels. The loss of syndecan-1 expression was caused by shedding of syndecan-1 (which will be explained later) as revealed by increased levels of soluble syndecan-1 (sSyndecan-1) in the conditioned medium of the stimulated cells (Day et al., 2003). The result of TNF-α in this investigation is different from the results in the NMuMG epithelial cells so the influence of TNF-α might be different depending on the type of epithelial cell.
The third study was performed by Jalkanen et al. in keratinocytes. They showed that syndecan-1 could be induced in keratinocytes by epidermal growth factor (EGF). During this investigation they also identified a novel FGF-inducible response element (FiRE) on the gene of syndecan-1.
FiRE is in keratinocytes also activated by EGF and the activation of FiRE in adult tissues is restricted to migrating keratinocytes of healing wounds. The FiRE might provide a powerful tool for studies on growth factor specificity and regulation of regeneration of tissues in the future (Jaakkola & Jalkanen, 1999).
Cytokines which regulate the expression of syndecan-1 in epithelial cells are TGF-β, TNF-α, IL-1β and EGF. TGF- β and EGF improve the syndecan-1 expression; TNF-α and IL-1β reduce the syndecan-1 expression.
Shedding
All heparan sulfate proteoglycans (including syndecan-1) can be shed from the cell surface, resulting in soluble PGs that presumably retain all the binding properties of their parent molecules (Bernfield et al., 1999). Syndecan-1 can be shed by various membrane-associated matrix metalloproteinases (MMPs) including MMP-7 (Li, Park, Wilson, & Parks, 2002) , MMP-9 (Brule et al., 2006) and MMP-14 (Endo et al., 2003). Recently investigation showed that a disintegrin-like metalloproteinase ADAM17 was also involved in shedding of syndecan-1. When lung epithelial cells were treated with TNF-α/IFN-γ shedding of syndecan-1 was induced. This
13 enhanced shedding of syndecan-1 was not related to gene induction of syndecans or ADAM17, but rather due to increased ADAM17 activity. Both constitutive and induced syndecan shedding was prevented by the ADAM17 inhibitor. ADAM17 may therefore be an important regulator of syndecan functions on inflamed lung epithelium and maybe also in other epithelium (Pruessmeyer et al., 2010).
All syndecan members are constitutively shed to some extent as part of their normal turn-over.
Yet, shedding of the syndecan core proteins can be accelerated. Shedding of syndecan-1 from epithelial is accelerated by direct proteolytic cleavage (thrombin, plasmin), by cellular stress (mechanical, heat shock, hyperosmolarity) acting through the Jun N-terminal kinase/stress- activated protein kinase (JNK/SAPK) pathway (Jalkanen, Rapraeger, Saunders, & Bernfield, 1987) and by activation of several other intracellular signaling pathways. These include phorbol ester stimulation of PKC (Subramanian, Fitzgerald, & Bernfield, 1997), pervanadate inhibition of protein tyrosine phosphatases (Reiland et al., 1996) and EGF and thrombin receptor activation of the extracellular signal-regulated protein kinase (ERK) pathway (Rapraeger et al., 1986).
Secreted products of certain bacterial pathogens also accelerate shedding (Popova et al., 2006).
Shedding can rapidly reduce the syndecan-1 expression on the cell surface. Reducing the expression of syndecan-1 on the cell surface leads to less responsive cells, since syndecan-1 is a co-receptor for many cytokines and growth factors. The resulting biologically active soluble syndecan-1 (sSynd-1) can function in an autocrine or paracrine manner by binding growth factors and cytokines and then binding to the corresponding receptor. sSynd-1 can also bind to ECM components, including fibrillar, collagens, fibronectin and tenascin. Binding of sSynd-1 to ECM components limits their activity and terminates their influence (Bernfield et al., 1999).
There has not been performed any investigation about the function of sSynd-1 in kidney regeneration. However some investigators performed research on sSynd-1 in dermal wound repair and alveolar epithelial wound healing, which might also concern the epithelial cells in the kidney.
Study into sSynd-1 in dermal wound repair showed that mice who overexpressed syndecan-1 (Snd/Snd) had increased sSynd-1 levels and the shedding was prolonged in wounds from Snd/Snd mice. Wound closure, re-epithelialization, granulation tissue formation, and remodeling were delayed in these mice and cells in the granulation tissue and keratinocytes at wound edges showed markedly reduced proliferation rates. Syndecan-1 immunodepletion and further degradation experiments identified sSynd-1 as a dominant negative inhibitor of cell proliferation. The investigators concluded that sSynd-1 may enhance proteolytic activity and inhibit cell proliferation during wound repair (V. Elenius, Gotte, Reizes, Elenius, & Bernfield, 2004).
The second study in alveolar epithelial cells confirmed that sSynd-1 can inhibit epithelial wound healing. When sSynd-1 was added to wounded alveolar epithelial cells, the healing was significantly inhibited. The cells had a rounded, less adhered morphology after treatment with sSynd-1. Addition of sSynd-1 in Syndecan-1 knockdown cells did not significantly augment impaired wound healing response (Kliment et al., 2009).
Because inhibition of wound healing by sSynd-1 was showed in both investigations, the expectation is that sSynd-1 also inhibits wound healing in the kidney. To confirm this expectation, more investigation is needed.
14
5. DISCUSSION
Investigations showed that syndecan-1 has an important influence on kidney regeneration. It is capable of protecting and repairing damaged kidney cells after renal injury. To stimulate regeneration after renal injury, syndecan-1 should thus be up regulated. There are two options for up regulating syndecan-1 expression.
The first option to up regulate syndecan-1 expression is all-trans retinoic acid (ATRA). ATRA is the acid form of vitamin A and it has been shown to up regulate syndecan-1 expression in lung cancer epithelial cells and therefore it might also be able to up regulate syndecan-1 in kidney epithelial cells (Ramya, Siddikuzzaman, & Grace, 2012) and is available as an oral drug.
The second option for up regulating syndecan-1 is a n-3 polyunsaturated fatty acids (n-3 PUFA) diet. Investigation showed that diets enriched in n-3 PUFA (docosahexaenoic acid) are associated with a lower incidence of cancers. This lower incidence of cancer was associated by up regulation of syndecan-1 and docosahexaenoic acid thus up regulates syndecan-1 (Hu et al., 2010). The effect of n-3 PUFA on syndecan-1 levels was also confirmed in another investigation (H. Sun et al., 2011).
As mentioned before syndecan-1 can also be shed from the cell surface. This leads to less responsive cells, since syndecan-1 is a co-receptor for many cytokines and growth factors. Due to the less responsiveness the cells are probably also less activated after stimulation with regenerative stimuli to regenerate. The resulting biologically active sSynd-1 can function in an autocrine or paracrine manner or can bind to ECM components, limiting the activity and terminating the influence of syndecan-1. Investigations about sSynd-1 showed that sSynd-1 inhibits cell proliferation and thus results in impaired wound healing response after injury. For achieving more regeneration after renal injury shedding should thus be avoided.
Avoidance of syndecan-1 shedding from oxidative stress can be achieved by the antioxidant enzyme extracellular superoxide dismutase (EC-SOD). EC-SOD null mice had increased sSynd-1 levels after (doxorubicin-induced) oxidative injury compared to wild-type. In the future EC-SOD might be given to humans to avoid shedding of syndecan-1 and induce regeneration (Kliment &
Oury, 2011).
In two investigations was showed that shedding of syndecan-1 can also be avoided by tissue inhibitor of metalloproteinase-3 (TIMP3). It should be investigated if it is save and whether it is possible to up regulate TIMP3 in the future to induce regeneration (Anand-Apte et al., 1996;
Fitzgerald, Wang, Park, Murphy, & Bernfield, 2000).
The last option for reducing syndecan-1 shedding is using a ADAM17 inhibitor. There are many different ADAM17 inhibitors and they are used in preclinical trials, however after more than a decade no single ADAM17 inhibitor has passed the Phase II clinical trials. More research work on ADAM17 inhibitors is needed to ensure that they will pass the Phase II clinical trials in the future (DasGupta, Murumkar, Giridhar, & Yadav, 2009).
Syndecan-1 seems very important in regulating the regeneration in the kidney. There are however other factors known which can influence this regeneration (Wnt-7b and CSF-1). Wnt- 7b is a ligand of the Wnt signaling pathway that is produced by macrophages. It seems to have an important role in regeneration of the kidney too, since Wnt-7b stimulates cells to pass the G2 checkpoint of the cell cycle. If the cells won’t pass the G2 checkpoint they will go in apoptosis. So
15 without Wnt-7b proliferation of the cells is not possible. Since most of the recovery capacity of the kidney comes from proliferating of the intrinsic kidney cells, there will probably be not much regeneration if Wnt-7b is absent (Lin et al., 2010).
The other factor which can influence regeneration of the kidney is produced by tubule epithelial cells and is called Colony Stimulating factor 1 (CSF-1). In a study where CSF-1 was injected after ischemic renal injury improved tubule pathology and function were found. There was also less renal fibrosis, more tubule proliferation and the apoptosis of tubule epithelial cells was suppressed. CSF-1 can bind to CSF-1 receptors on macrophages and stimulate the regenerative capacity of macrophages. Mechanisms are unknown but are thought to be regulated via macrophage-stimulating protein (MSP) because in vitro MSP stimulates tubule epithelial cell proliferation (Menke et al., 2009). More research to confirm the role of CSF-1 in renal regeneration and to find out the mechanism behind it is needed but it is clear that it has an influence on regeneration of the kidney.
Syndecan-1 offers new starting points for therapies for people with chronic kidney failure. It might help a number of regenerative cytokines (HGF, Wnt-7b, HB-EGF) by acting as a co- receptor for these factors. Thereby it can help the cells in the kidney to carry out their regenerative function and regeneration of the kidney after renal injury will be stimulated.
If patients however lack other functions (like Wnt-7b production by macrophages), the questions rises if syndecan-1 is really that important. Syndecan-1 can then be up regulated, but there will probably be hardly any regeneration, since the epithelial cells cannot pass the G2 checkpoint of the cell cycle. In that case up regulation of Wnt-7b is a more important point of investigation. The discovery of the importance of syndecan-1 in regeneration is promising, but the Wnt-7b ligand seems to be very important too.
16
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