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Keywords:

  • angiotensin II;
  • angiotensin receptors;
  • cell differentiation;
  • neuroprotection;
  • peroxisome proliferator-activated receptor gamma

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The angiotensin type 2 (AT2) receptor has been previously demonstrated to exert neuroprotective actions possibly by inducing neuronal cell differentiation involving neurite outgrowth. The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ) is an important transcriptional regulator of cell differentiation. The aim of the present study was to clarify whether PPARγ is involved in AT2-receptor-mediated morphological neuronal cell differentiation. To investigate AT2-receptor-mediated morphological neuronal cell differentiation, rat pheochromocytoma cells (PC12W cells) expressing AT2 but not AT1 receptors, were stimulated with angiotensin II (Ang II, 100 nmol/L) ± the PPARγ antagonists GW9662 (3 µmol/L) and bisphenol A diglycidyl ether (BADGE, 1 µmol/L), and neurite outgrowth of these cells was assessed. Ang II induced neurite outgrowth by 19 ± 1.6-fold (p < 0.01). Antagonizing PPARγ activity by GW9662 or BADGE potently blocked Ang II-induced neurite outgrowth (Ang II + GW9662: 6.6 ± 1.5-fold, p < 0.05; Ang II + BADGE: 1.3 ± 0.7-fold, p < 0.01). AT2 receptor activation by Ang II markedly induced mRNA and protein expression of the PPARγ2 isoform and enhanced ligand-induced PPARγ activity in transactivation assays. In conclusion, the present study demonstrates that Ang II induces PPARγ expression and ligand-mediated PPARγ activity via AT2 receptor activation, which appears to be a crucial process in AT2 receptor mediated neurite outgrowth. AT2 receptor/PPARγ-dependent neurite outgrowth may play an important role during neuroprotective processes.

Abbreviations used:
Ang II

angiotensin II

AT1

receptor, angiotensin type 1 receptor

AT2

receptor, angiotensin type 2 receptor

BADGE

bisphenol A diglycidyl ether

LBD

ligand binding domain

PPAR

peroxisome proliferator-activated receptor

Sp1

specificity protein 1

Two main classes of angiotensin receptors, angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors have been identified by molecular cloning and pharmacological studies (de Gasparo et al. 2000). Most of the physiological angiotensin II (Ang II) effects, such as blood pressure and fluid homeostasis regulation, have been attributed to AT1 receptor activation (de Gasparo et al. 2000). However, the AT2 receptor is gaining attention as an opponent to the AT1 receptor by exerting opposite effects in the cardiovascular system, e.g. AT2 receptor-mediated vasodilation and anti-proliferation (Stoll et al. 1995; Arima et al. 1997; Gohlke et al. 1998). AT2 receptors are expressed in various regions of the human brain, including substantia nigra, putamen, caudate nucleus and cerebellum, and the expression is up-regulated after cerebral ischemia (Barnes et al. 1993; MacGregor et al. 1995; Li et al. 2005). In the CNS and peripheral nerves, the AT2 receptor has been previously described to exert neuroregenerative and neuroprotective actions by stimulating neuronal cell differentiation and neurite outgrowth (Laflamme et al. 1996; Meffert et al. 1996; Lucius et al. 1998; Cote et al. 1999; Gendron et al. 2003; Reinecke et al. 2003). The underlying mechanisms of AT2 receptor-mediated neuroregeneration/protection are partially understood. We have previously demonstrated that AT2 receptors are exclusively expressed in neurones, where they promote neurite outgrowth (Li et al. 2005). AT2 receptor-stimulated neurite formation involves nitric oxide and cGMP production and induces the formation of microtubules (Stroth et al. 1998; Gendron et al. 2002; Zhao et al. 2003).

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study has demonstrated that hypertensive patients receiving the AT1 receptor antagonist losartan had a 25% lower rate of stroke than the atenolol-treated group, implicating neuroprotective effects of AT1 receptor antagonists (Dahlof et al. 2002). It has been shown that selective AT1 receptor blockade redirects available Ang II to the AT2 receptor mediating beneficial effects (Wu et al. 2001). Therefore, AT2 receptor-mediated neurotrophic actions may be an important mediator of neuroprotection during AT1 receptor blockade.

The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the PPAR superfamily of nuclear hormone receptors, which function as transcriptional regulators in a variety of cells (Desvergne and Wahli 1999). Activated by its ligands such as prostaglandins or synthetic insulin-sensitizing thiazolidinediones/glitazones, PPARγ functions as a transcriptional regulator of multiple genes, thereby promoting the differentiation process of various cell types (Tontonoz et al. 1995, 1998). Ligand-activated PPARγ is the ‘master’ regulator of adipocyte differentiation. In the CNS, PPARγ is expressed in microglial cells, astrocytes and neuronal cells (Heneka et al. 2001). Recently, various PPARγ agonists have been shown to exert neuroprotective effects in different neurological disease models (Alzheimer's and Parkinson's disease, multiple sclerosis and cerebral ischemia) indicating a beneficial role of PPARγ in the CNS (Heneka et al. 2001; Dehmer et al. 2004; Shimazu et al. 2005). In addition, activation of the other PPAR isoform, PPARα, reduces the susceptibility to stroke in apolipoprotein E-deficient mice, underscoring the importance of these receptors in neuroprotection (Deplanque et al. 2003).

Interactions between the renin-angiotensin system and PPARγ have been recently demonstrated in vivo (Tham et al. 2002; Kintscher et al. 2004). Ang II infusion in apolipoprotein E-deficient mice significantly reduced aortic PPARγ mRNA and protein expression, a process likely mediated by activation of the AT1 receptor (Tham et al. 2002). The role of the AT2 receptor in the regulation of PPARγ expression and function has not been studied.

To elucidate further mechanisms of AT2 receptor-mediated neuroregeneration we studied the function of PPARγ in AT2 receptor-dependent neurite formation/morphological cell differentiation in a neuronal cell model, PC12W cells.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Cell culture

PC12W cells were cultured as previously described (Zhao et al. 2003).

Evaluation of neurite outgrowth

Morphological PC12W cell differentiation and evaluation of neurite outgrowth was performed as previously described (Zhao et al. 2003). Cells were treated for six consecutive days with Ang II (100 nmol/L) ± the PPARγ antagonists GW9662 (3 µmol/L) and bisphenol A diglycidyl ether (BADGE, 1 µmol/L), or with the PPARγ agonist pioglitazone (10 µmol/L) alone (Wright et al. 2000; Fu et al. 2001). Toxic effects of the compounds have been excluded by trypan blue staining experiments. Outgrown neurites were classified into two groups: medium neurites (10–20 mm = 5–10 µm) and large neurites (> 20 mm = > 10 µm). Results are presented as x-fold induction (mean of medium and large neurites) over vehicle/dimethylsulfoxide-treated control ± SEM.

Semiquantitative reverse transcription–polymerase chain reaction

RT–PCR was performed as previously described (Zhao et al. 2003). The sequences of specific sets of PCR primers were as followed: PPARγ2: sense 5′-TGTTGACCCAGAGCATGGTGC-3′, antisense 5′-AACCCTTGCATCCTTCACAAGC-3′; PPARγ1 sense 5′-ACAAGACTACCCTTTACTGAAATTACC-3′, antisense 5′-GTCTTCATAGTGTGGAGCAGAAATGCTG-3′, β-actin sense 5′-ATGGATGATGATATCGCCGCG-3′, antisense 5′-CATGAAGCATTTGCGGTGGACGATGGAGGGGCC-3′. Autoradiographic signals were densitometrically quantified using a Bio-Rad Image System (Bio-Rad Laboratories, Hercules. CA, USA).

Western immunoblotting

PC12W cells were exposed to Ang II. After the indicated time interval, protein isolation, electrophoresis and blotting were performed as previously described (Kintscher et al. 2002b). Blots were incubated with a specific antibody recognizing both PPARγ isoforms (1:1000 dilution, sc-7196, Santa Cruz Biotechnology, Santa Cruz, CA, USA), Annexin II (1:3000 dilution, A14020, BD Transduction Laboratories, San Diego, CA, USA), or or β-actin (1:5000 dilution, A5441, Sigma-Aldrich, St Louis, MO, USA). Immunoreactive bands were visualized using horseradish peroxidase-conjugated secondary antibodies (1:1000 dilution). The peroxidase reaction was developed using an enhanced chemiluminescence detection system (ECL, Amersham Corp., Piscataway, NJ, USA). Band intensity was analysed by densitometry.

Transfection and luciferase assay

Transient transfection and luciferase assays were performed as previously described (Kintscher et al. 2002b). PC12W cells were transfected using Lipofectamine 2000 (Invitrogen). After stimulation with Ang II (100 nmol/L) for 72 h, cells were transfected with pGal4-hPPARγDEF [hPPARγ ligand binding domain (LBD) fused to Gal4 DBD] and pGal5-TK-pGL3 provided by Bart Staels (UR 545 INSERM, Institut Pasteur de Lille, France), and pRL-CMV, a renilla luciferase control reporter vector. After 4 h, transfection medium was replaced by 0.5% fetal bovine serum, Dulbecco's modified Eagle's medium plus Ang II (100 nmol/L), PD 123319 (10 µmol/L) and pioglitazone (100 nmol/L), or vehicle (dimethylsulfoxide) and luciferase activity was measured after 24 h.

Statistics

Analysis of variance (followed by post hoc bonferroni test) or t-tests were performed for statistical analysis, as appropiate. Values of p < 0.05 were considered to be statistically significant. Data are expressed as mean ± standard error of the mean (SEM).

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Peroxisome proliferator-activated receptor gamma antagonism inhibits angiotensin II-induced neurite outgrowth

PC12W cells used for the present experiments exclusively expressed AT2 receptors as confirmed by RT–PCR and binding assays (data not shown). AT2 receptor activation by Ang II (100 nmol/L) stimulated neurite outgrowth in PC12W cells by 19 ± 1.6-fold (p < 0.01 vs. unstimulated cells) (Figs 1a and b). Antagonizing PPARγ activity by pretreatment with GW9662 or BADGE potently blocked Ang II-induced neurite outgrowth (Ang II + GW9662: 6.6 ± 1.5-fold, p < 0.05 vs. Ang II alone; Ang II + BADGE: 1.3 ± 0.7-fold, p < 0.01 vs. Ang II alone), indicating that PPARγ activation is required for AT2 receptor-mediated neurite formation (Figs 1a and b). Treatment of PC12W cells with the PPARγ agonist pioglitazone alone induced neurite outgrowth by a maximum of 8.1 ± 1.7-fold (10 µmol/L, p < 0.05 vs. unstimulated cells) (data not shown).

image

Figure 1. Peroxisome proliferator-activated receptor gamma (PPARγ) antagonism inhibits angiotensin II (Ang II)-induced neurite outgrowth. PC12W cells were differentiated in the absence or presence of Ang II (100 nmol/L) ± the PPARγ antagonists GW9662 (GW, 3 µmol/L) and bisphenol A diglycidyl ether (BADGE, 1 µmol/L). (a) Outgrown neurites were classified into two groups: medium neurites (10–20 mm =5–10 µm) and large neurites (> 20 mm = > 10 µm). Results are presented as x-fold induction (mean of medium and large neurites) over vehicle/dimethylsulfoxide-treated control ± SEM. *p < 0.05, **p < 0.01 vs. unstimulated cells; #p < 0.05, ##p < 0.01 vs. Ang II alone. (b) Cells were treated as described under (a). Representative photographs from morphological PC12W cell differentiation/neurite outgrowth in the absence or presence of Ang II (100 nmol/L) ± the PPARγ antagonists GW9662 (GW: 3 µmol/L) and BADGE (1 µmol/L) are shown.

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Angiotensin II induces peroxisome proliferator-activated receptor gamma 2 expression via angiotensin type 2 receptor activation

To further elucidate the role of PPARγ in Ang II-induced neurite formation in PC12W cells, we next studied the regulation of PPARγ1 and γ2 expression by Ang II. Ang II (100 nmol/L) markedly induced PPARγ2 mRNA expression, reaching a maximum after 8 h (9.4 ± 0.7-fold vs. unstimulated cells, p < 0.01) (Fig. 2a). Differentiated 3T3-L1 adipocytes served as a positive control. PPARγ1 mRNA was not detectable in unstimulated PC12W cells and was not affected by Ang II (data not shown). Consistent with the induction of PPARγ2 mRNA expression by Ang II, PPARγ protein expression was also stimulated by Ang II (100 nmol/L) with a maximum after 36 h (Fig. 2b). To confirm that the regulation of PPARγ2 by Ang II is solely through AT2 receptor activation, PC12W cells were pretreated with the selective AT2 receptor antagonist PD 123319 (10 µmol/L) followed by Ang II (100 nmol/L) stimulation. AT2 receptor blockade by PD 123319 completely inhibited Ang II-induced PPARγ2 mRNA expression (Fig. 2c).

image

Figure 2. Angiotensin II (Ang II) induces peroxisome proliferator-activated receptor gamma (PPARγ) expression via angiotensin type 2 receptor (AT2 receptor) activation. (a) PC12W cells were treated with Ang II (100 nmol/L). After the indicated time intervals, total mRNA was isolated and RT–PCR was performed as described under methods. β-Actin gene was used as a control to assure equal loading. Differentiated 3T3-L1 adipocytes (Adip.) served as a positive control. Upper panels: representative RT–PCRs from three separate experiments. Graph: densitometric analysis of PPARγ2/β-actin gene expression is shown as x-fold induction over unstimulated cells. Results are presented as mean ± SEM. *p < 0.05, **p < 0.01 vs. unstimulated cells. (b) PC12W cells were treated with Ang II (100 nmol/L). After the indicated time intervals, protein was isolated and western immunoblotting experiments were performed as described in the methods section. Representative immunoblots for PPARγ and β-actin from three separate experiments are shown. Graph: densitometric analysis of PPARγ protein expression is shown as x-fold induction over unstimulated cells. Results are presented as mean ± SEM. *p < 0.05 vs. unstimulated cells. (c) PC12W cells were treated with Ang II (100 nmol/L) ± selective AT2 receptor antagonist PD 123319 (PD, 10 µmol/L) for 8 h and experiments were performed as described under (a). Upper panels: representative RT–PCRs from three separate experiments. Graph: densitometric analysis of PPARγ2/β-actin gene expression is shown as x-fold induction over unstimulated cells. Results are presented as mean ± SEM. **p < 0.01 vs. unstimulated cells; #p < 0.05 vs. Ang II alone.

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Angiotensin II enhances ligand-induced peroxisome proliferator-activated receptor gamma activity via angiotensin type 2 receptor activation

To test whether AT2 receptor activation also regulates transcriptional activity of PPARγ, we assessed the ability of Ang II to activate the chimeric Gal4-DBD-hPPARγ-LBD fusion protein on a Gal4-dependent luciferase reporter in the presence of the PPARγ agonist pioglitazone in PC12W cells. In this system, the activation of the reporter is solely mediated through activation of the transfected PPARγ LBD, and not depending on cellular PPARγ protein. Pretreatment of AT2-receptor-expressing PC12W cells with Ang II (100 nmol/L) markedly enhanced ligand-mediated PPARγ activation by 1.7 ± 0.3-fold [p < 0.05 vs. pioglitazone alone (100 nmol/L)], which was completely blocked by cotreatment with PD 123319 (10 µmol/L), demonstrating that AT2 receptor activation enhances ligand-induced PPARγ activation (Fig. 3).

image

Figure 3. Angiotensin II (Ang II) enhances ligand-induced peroxisome proliferator-activated receptor gamma (PPARγ) activity via angiotensin type 2 receptor (AT2 receptor) activation. After Ang II (100 nmol/L) ± PD 123319 (PD, 10 µmol/L) stimulation, PC12W cells were transiently transfected with the pGal4-hPPARγDEF and pGal5-Tk-pGL3 reporter followed by stimulation with pioglitazone (100 nmol/L). Firefly luciferase activity was measured after 24 h and normalized with activity of cotransfected renilla luciferase. Experiments were repeated three times and results are presented as mean ± SEM. *p < 0.05 vs. piogliatzone-treated cells; #p < 0.05 vs. Ang II/piogliatzone-treated cells.

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Angiotensin II induced-Annexin II expression is blocked by peroxisome proliferator-activated receptor gamma antagonism

To elucidate further mechanisms of Ang II-induced neuritogenesis via PPARγ, we examined the regulation of a major modulator of neurite outgrowth in PC12 cells, Annexin II. Annexin II is a phospholipid-binding membrane protein enhancing the generation of plasmin on the cell surface, which is required for the outgrowth of neurites (Jacovina et al. 2001). Furthermore, de novo transcription of Annexin II seems to be essential for neuritogenesis.

Ang II (100 nmol/L) prominently induced Annexin II protein expression in a time-dependent manner, reaching a maximum after 8 h, whereupon it remained steady for 36 h (Fig. 4). Consistently with the function of PPARγ in Ang II-induced neurite outgrowth, blockade of PPARγ activity by GW9662 prevented Ang II-mediated up-regulation of Annexin II, suggesting that Annexin II might be mechanistically involved in Ang II/PPARγ-mediated neuritogenesis (Fig. 4). Pioglitazone alone did not affect Annexin II expression in PC12 cells (data not shown).

image

Figure 4. Angiotensin II (Ang II) induced-Annexin II expression is blocked by peroxisome proliferator-activated receptor gamma (PPARγ) antagonism. PC12W cells were treated with Ang II (100 nmol/L) ± the PPARγ antagonist GW9662 (GW, 3 µmol/L). After the indicated time intervals, protein was isolated and western immunoblotting experiments were performed as described in the methods section. Representative immunoblots for Annexin II and β-actin from three separate experiments are shown. Densitometric analysis of Annexin II protein expression is shown as x-fold induction over unstimulated cells. Results are presented as mean ± SEM. **p < 0.01 vs. unstimulated cells; #p < 0.05 vs. Ang II (8 h) alone.

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Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The present study demonstrates that Ang II induces PPARγ2 expression and ligand-mediated PPARγ activity in PC12W cells via AT2 receptor activation. In parallel, inhibition of PPARγ activity blocked Ang II-induced neurite formation, which was associated by a blockade of Ang II-mediated up-regulation of Annexin II, an important regulator of neuritogenesis.

Neuritogenesis is a morphological marker of the differentiation process in PC12 cells (Tischler and Greene 1975). PPARγ has been demonstrated to be a major regulator of cell differentiation in adipocytes and monocytes/macrophages (Tontonoz et al. 1994, 1998). Ligand activation of PPARγ is essentially required for the differentiation of these cells. Consistent with the inhibitory effect of PPARγ antagonists on AT2 receptor-stimulated morphological PC12W cell differentiation in our study, PPARγ antagonism inhibits the differentiation of adipocytes (Wright et al. 2000). In addition to its crucial role in adipocyte/macrophage differentiation, PPARγ seems to be required for AT2 receptor-mediated neuronal differentiation of PC12W cells.

It has been shown previously that ligand-activated PPARγ does not affect PC12 cell differentiation induced by nerve growth factor, implicating that the involvement of PPARγ in neuronal cell differentiation seems to be specific for Ang II (Jung et al. 2003). This is further corroborated by the regulation of PPARγ expression by Ang II. In our study, PPARγ was almost undetectable in unstimulated PCW12 cells, which is consistent with other studies (Jung et al. 2003). Low levels of PPARγ in PC12W cells may explain the failure of ligand-activated PPARγ to regulate neurite formation induced by other growth factors. (Satoh et al. 1999; Jung et al. 2003). We could show that Ang II stimulates the expression of the endogenous PPARγ2 isoform, which is usually abundant in, and primarily restricted to, adipose tissue. We have recently shown that transforming growth factor-β induces PPARγ2 expression in monocytes, whereas stimulation with phorbol 12-myristate 13-acetate, failed to induce PPARγ2 (Kintscher et al. 2002a). Together, regulation of PPARγ2 expression in non-adipose cells appears to be highly specific for certain growth factors (e.g. Ang II) and may explain the unique role for PPARγ in PC12W cell differentiation induced by Ang II.

The present study demonstrates for the first time that AT2 receptor activation by Ang II induces ligand-dependent PPARγ activity. We utilized the Gal4-DBD-hPPARγ-LBD reporter system to assess PPARγ activity. Activation of the system is dependent on binding of a ligand to the PPARγ-LBD followed by a conformational change, and nuclear coactivator recruitment to facilitate induction of the Gal4-DBD luciferase reporter. AT2 receptor activation markedly enhanced ligand-induced activation of the system. This could be mediated by the following mechanisms.

  • (i) 
    AT2 receptor activation may enhance binding of nuclear PPARγ-coactivators. Stimulation of the tyrosine hydroxylase promoter by Ang II has been shown to be associated with an enhanced binding of the p300/CREB-binding protein complex to corresponding promoter elements (Peng et al. 2002). The p300/CREB-binding protein complex is known as a PPARγ coactivator complex (Rosenfeld and Glass 2001).
  • (ii) 
    AT2 receptor activation may produce additional endogenous PPARγ ligands. It has already been shown that Ang II can induce the release of endogenous PPAR activators from the prostaglandin family in vivo, demonstrating a potential link between endogenous PPARγ ligand production and Ang II (Darimont et al. 1994).

Taken together, potential molecular explanations of AT2 receptor-induced PPARγ activation do exist, however, future experimental studies are surely required to prove the relevance of these processes.

To identify potential molecular targets involved in AT2 receptor/PPARγ-mediated neuritogenesis, we studied the effect of Ang II stimulation on the expression of Annexin II in PC12W cells. Annexin II is a phospholipid-binding protein located on the cell surface of neuronal cells, where it is required for neuritogenesis and cell differentiation. The up-regulation of Annexin II expression by growth factors is a prerequisite for the outgrowth of neurites in PC12 cells (Jacovina et al. 2001). The underlying mechanism of the central role of Annexin II in neuritogenesis includes the activation of plasminogen resulting in increased generation of plasmin (Jacovina et al. 2001). In addition to its role in fibrinolysis, the serine protease plasmin has been demonstrated to degrade major components of the neuronal extracellular matrix (Chen and Strickland 1997). Degradation of the extracellular matrix barrier is essential for neurite outgrowth. In the present study, Ang II potently stimulated Annexin II protein expression in PC12W cells, which was prominently blocked by inhibition of PPARγ activation. These data identify a new potential mechanism of AT2 receptor-mediated neuritogenesis involving PPARγ-mediated target gene regulation. The involvement of PPARγ activation appears to be highly specific for AT2-receptor-mediated Annexin II induction, since in the absence of AT2-receptor activation, pioglitazone failed to stimulate Annexin II expression. Classical PPAR response elements have not yet been described in the Annexin II promoter (Fey et al. 1996). However, the Annexin II promoter contains a number of specificity protein 1 (Sp1)-binding sites (Fey et al. 1996). PPARγ has been recently reported to enhance specificity protein 1 (Sp1) binding to its corresponding promoter elements, which may provide a potential molecular mechanism for the AT2-receptor/PPARγ-mediated effects observed in our study (Sassa et al. 2004). The present study identifies a new molecular mechanism of AT2 receptor-mediated neurite outgrowth involving the activation of PPARγ. AT2 receptors gain functional importance during selective AT1 receptor blockade by redirecting the available Ang II to the AT2 receptor (Wu et al. 2001). AT1 receptor antagonists have been demonstrated to exert neuroprotective effects in animals and clinical studies (Dai et al. 1999; Dahlof et al. 2002). AT2 receptor/PPARγ-dependent neuritogenesis may therefore provide an important mechanism of neuroprotection during AT1 receptor blockade.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

ThU and UK are supported by the Deutsche Forschungsgemeinschaft (GK 754-II).

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  3. Materials and methods
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  5. Discussion
  6. Acknowledgements
  7. References
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