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Cell Biology |
1-Induced Mitogen-Activated Protein Kinase Activation and Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells
* Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea; Department of Medicinal Plant Resources, Mokpo National University, Jeonnam, Korea; National Institute of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; and Ewha Womans University College of Pharmacy, Seoul, Korea
Address correspondence to: Dr. Hunjoo Ha, Ewha Womans University College of Pharmacy, 11-1 Daehyun-dong, Sedaimun-gu, Seoul 120-750, Korea. Phone: +82-2-3277-4075; Fax: +82-2-3277-2851; E-mail: ha{at}hkl.ac.kr or hha{at}ewha.ac.kr
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Abstract |
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1 is the key inducer of EMT. Phosphorylation of Smad proteins and/or mitogen-activated protein kinases (MAPK) is required for TGF-1–induced EMT. Because reactive oxygen species (ROS) are involved in TGF-1 signaling and are upstream signaling molecules to MAPK, this study examined the role of ROS in TGF-1–induced MAPK activation and EMT in rat proximal tubular epithelial cells. Growth-arrested and synchronized NRK-52E cells were stimulated with TGF-1 (0.2 to 20 ng/ml) or H2O2 (1 to 500 µM) in the presence or absence of antioxidants (N-acetylcysteine or catalase), inhibitors of NADPH oxidase (diphenyleneiodonium and apocynin), mitochondrial electron transfer chain subunit I (rotenone), and MAPK (PD 98059, an MEK [MAP kinase/ERK kinase] inhibitor, or p38 MAPK inhibitor) for up to 96 h. TGF-1 increased dichlorofluorescein-sensitive cellular ROS, phosphorylated Smad 2, p38 MAPK, extracellular signal-regulated kinases (ERK)1/2, 
-smooth muscle actin (-SMA) expression, and fibronectin secretion and decreased E-cadherin expression. Antioxidants effectively inhibited TGF-1–induced cellular ROS, phosphorylation of Smad 2, p38 MAPK, and ERK, and EMT. H2O2 reproduced all of the effects of TGF-1 with the exception of Smad 2 phosphorylation. Chemical inhibition of ERK but not p38 MAPK inhibited TGF-1–induced Smad 2 phosphorylation, and both MAPK inhibitors inhibited TGF-1- and H2O2-induced EMT. Diphenyleneiodonium, apocynin, and rotenone also significantly inhibited TGF-1–induced ROS. Thus, this data suggest that ROS play an important role in TGF-1–induced EMT primarily through activation of MAPK and subsequently through ERK-directed activation of Smad pathway in proximal tubular epithelial cells. |
Introduction |
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-smooth muscle actin (-SMA) expression and actin reorganization, (3) disruption of tubular basement membrane, and (4) enhanced cell migration and invasion into the interstitium
Tubular EMT can be induced by TGF-1 (5,7–10), advanced-glycation end products (11,12), and angiotensin II (13), but TGF-1 is probably the key inducer of EMT because TGF-1 signaling is sufficient to induce EMT in cultured epithelial cells (9,10). Whereas TGF-1 responses are initiated by the interaction of TGF-1 with cell surface receptors (14), the intracellular signaling pathways involved in EMT are complex and incompletely understood. In a normal rat tubular epithelial cell line NRK-52E, Li et al. (15) showed that TGF-1 induced Smad 2 phosphorylation and resulted in the transformation of epithelial cell into myofibroblast phenotype with the loss of E-cadherin and de novo expression of -SMA and collagens I, III, and IV and that overexpression of Smad 7 resulted in marked inhibition of TGF-–induced Smad 2 activation with the prevention of EMT and collagen synthesis. In addition to Smad pathway, Rho A (16,17) and mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinases (ERK) (18–21), p38 MAPK (22,23), and c-Jun N-terminal kinases (JNK) (24) are involved in TGF-1–induced EMT. There is a cross-talk between ERK and Smad 2 (10,25). Elevated ERK activity can enhance Smad activity, and ERK inhibition reduces TGF-1–stimulated Smad phosphorylation as well as collagen production and promoter activities, suggesting that ERK activity is necessary for an optimal response to TGF-1 (25)
Reactive oxygen species (ROS) have been shown to mediate TGF-1–induced cellular responses in various cells (26–32). We (33) recently demonstrated that TGF-1 upregulates plasminogen activator inhibitor-1 expression in glomerular mesangial cells through ROS. ROS are known to activate MAPK (34). However, it is not known whether ROS are involved in EMT. We therefore examined whether TGF-1–induced EMT is mediated by ROS-MAPK pathway. For this purpose, we measured cellular ROS after stimulation with TGF-1, examined the effect of antioxidants on TGF-1–induced MAPK activation and EMT, and finally compared the effect of H2O2 with that of TGF-1. We also examined the source and type of TGF-1–induced cellular ROS and the cross-talk between MAPK and Smad 2
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Materials and Methods |
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Cell Culture and Treatment
Rat proximal tubular epithelial cell line NRK52E was purchased from American Type Culture Collection (Rockville, MD). Cells were cultured in DMEM (Life Technologies BRL, Gaithersburg, MD) that contained 5% FBS (Life Technologies BRL), 100 U/ml penicillin, 100 µg/ml streptomycin, 44 mM NaHCO3, and 14 mM HEPES
Cells were cultured at a density of 8 x 104 cells/well in six-well culture plates. Near confluent NRK-52E cells were incubated with serum-free media for 24 h to arrest and synchronize the cell growth. After this time period, the media were changed to fresh serum-free media that contained various concentrations of recombinant human TGF-1 (R&D Systems, Minneapolis, MN) or H2O2. In some experiments, cells were pretreated with antioxidants (5 mM N-acetylcysteine [NAC] and 500 U/ml catalase), NADPH oxidase inhibitors (100 nM diphenyleneiodonium [DPI] and 100 µM apocynin), mitochondrial electron transfer chain subunit I inhibitor (rotenone 1 µM), 5 µM p38 MAPK inhibitor (2-[-4-chlorophenyl]-4-[4-fluorophenyl]-5-pyridine-4-yl-1,2-dihydropyrazol-3–1; Calbiochem, San Diego, CA), or 50 µM PD98059, a known MEK (MAP kinase/ERK kinase) inhibitor (Calbiochem) for 1 h before the addition of TGF-1 or H2O2. The effective concentrations of antioxidants, NADPH oxidase inhibitors, and rotenone were decided on the basis of our previous data (33,35) and MAPK inhibitors from our preliminary study. Cells were processed for measurement of cellular ROS and expression of E-cadherin, -SMA, ERK, p38 MAPK, and Smad 2 at the end of incubation period as described below
Assay of Cellular Reactive Oxygen Species
Dichlorofluorescein (DCF)-sensitive cellular ROS in NRK52E cells were measured by a FACS (Becton Dickinson, Mountain View, CA) as described previously (33). In brief, cells in various time points after stimulation with serum-free TGF-1 or H2O2 were washed with serum-free and phenol red-free DMEM and loaded with 5 µM 5-(an-6)-chloromethyl-2`,7`-dichlorodihydrofluorescein diacetate (Molecular Probes, Eugene, OR). After incubation for 20 min in the dark, the cells were washed with PBS, detached, and resuspended in 1 ml of PBS. Cellular ROS in 10,000 cells as a result of the oxidation of 2`,7`-dihydrofluorescein was measured (excitation, 488 nm; emission, 515 to 540 nm)
Cellular superoxide anion and peroxinitrite were measured using dihydroethidine (36) and dihydrorhodamine 123 (DHR) (37), respectively. Dihydroethidine is cell permeable and reacts with O2·– to form ethidium, which in turn interacts with DNA, providing fluorescence at an excitation at 520 nm and an emission at 610 nm. DHR forms the fluorescence product rhodamine 123 upon oxidation by peroxides and notably ONOO–. Fluorescence was detected with emission at 530 nm and excitation at 485 nm and normalized to total cell protein and expressed as fold of control
Western Blot Analysis
At the end of incubation, cells were washed with PBS and lysed in 150 µl of lysis buffer of 20 mM Tris-HCl (pH 7.9), 137 mM NaCl, 5 mM EDTA, 1 mM EGTA, and 1% Triton-X that contained protease inhibitors for 10 min at 4°C. Conditioned media and cell lysates were centrifuged at 13,000 rpm at 4°C for 15 min to pellet cell debris, and the concentration of cellular protein was determined using Bio-Rad assay (Bio-Rad Laboratories, Hercules, CA). Samples with equal concentrations of cellular protein (20 µg) were mixed with a 5x sample buffer that contained 60 mM Tris-HCl (pH 6.8), 25% glycerol, 2% SDS, 0.1% bromophenol, and 0.2% 2-mercaptoethanol and was heated at 95°C for 10 min and separated on 10% SDS-polyacrylamide gels. After electrophoresis, the proteins were transferred onto a nitrocellulose membrane using a transblot chamber with Tris buffer (0.025 M Tris-HCl, 0.192 M glycine, and 20% MeOH). The membrane was blocked for 1 h at room temperature with 5% nonfat milk in TBS-Tween 20. Membranes were incubated at 4°C overnight with mouse mAb to E-cadherin (Becton Dickinson Labware; 1:2000), mouse anti–-SMA mAb (clone 1A4; 1:2000), rabbit polyclonal anti-phosphorylated and total ERK1/2 antibody (Cell Signaling, Beverly, MA; 1:1000), or rabbit polyclonal anti-phosphorylated and total p38 MAPK antibody (Cell Signaling; 1:1000) or anti-phosphorylated Smad 2 antibody (Calbiochem, San Diego, CA; 1:1000). After extensive washing in TBS-Tween 20, the membranes then were incubated with horseradish peroxidase–conjugated anti-mouse IgG or anti-rabbit IgG for 1 h at room temperature. After washing, the membranes were incubated with enhanced chemiluminescence system (ECL) detection kit (Amersham Life Science, Little Chalfont, UK). Positive immunoreactive bands were quantified densitometrically, normalized by -actin (for E-cadherin, -SMA, and phosphorylated Smad 2), total ERK1/2 (1:2000, for phosphorylated ERK), or total p38 MAPK (1:2000, for phosphorylated p38 MAPK) and compared with controls. For fibronectin secreted into the media, 5% polyacrylamide gel and peroxidase-conjugated rabbit anti-human fibronectin (DAKO A/S, Glostrup, Denmark; 1:2000) were used.
Statistical Analyses
All results are expressed as mean ± SE with n as the number of experiments. ANOVA was used to assess the differences between multiple groups. When the F statistic was significant, the mean values obtained from each group then were compared by Fisher least significant difference method. P < 0.05 was used as the criterion for a statistically significant difference
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Results |
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1 on E-Cadherin and -SMA Expression1 decreased E-cadherin expression and increased -SMA expression in a dose- (Figure 1, A and B) and a time-dependent manner (Figure 1, C and D) in NRK-52E cells. Statistically significant changes were observed at 10 ng/ml and from day 2 after TGF-1
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1 on p38 MAPK, ERK, and Smad 2 Activation1 at 10 ng/ml significantly increased phosphorylated p38 MAPK (Figure 2A) and ERK1/2 (Figure 2B) from 15 min, and this increase remained significant up to 2 h. TGF-1–induced Smad 2 phosphorylation was evident from 5 min under our experimental condition (Figure 2C)
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1 on Cellular ROS Generation: Source and Type of ROS1 at 10 ng/ml significantly increased DCF-sensitive cellular ROS in NRK-52E cells from 5 to 30 min (Figure 3A). Cellular ROS at 10 min after TGF-1 was two-fold higher than that of basal. Cellular ROS returned to basal level at 4 h after TGF-1. There was a slight but statistically significant increase in dihydrorhodamine-sensitive ROS (data not shown). There was, however, no significant increase in dihydroethidine-sensitive ROS (data not shown). Inhibitors of NADPH oxidase (100 nM DPI and 100 µM apocynin), an inhibitor of mitochondrial electron transfer chain subunit I (rotenone 1 µM), and antioxidants (5 mM NAC and 500 U/ml catalase) all significantly reduced TGF-1–induced DCF-sensitive cellular ROS (Figure 3B)
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1–Induced p38 MAPK, ERK, and Smad 2 Activation1–induced phosphorylation of p38 MAPK (Figure 4A), ERK1/2 (Figure 4B), and Smad 2 (Figure 4C). Neither NAC nor catalase affected basal phosphorylation of p38 MAPK, ERK1/2, and Smad2 (data not shown)
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1–Induced EMT1–induced downregulation of E-cadherin was effectively prevented by pretreatment with antioxidants NAC (5 mM) or catalase (500 U/ml; Figure 5A). Both NAC and catalase effectively inhibited TGF-1–induced upregulation of -SMA expression (Figure 5B). Pretreatment with 50 µM PD 98059, an MEK inhibitor, or 5 µM p38 MAPK inhibitor effectively prevented TGF-1–induced changes in E-cadherin (Figure 6A) and -SMA expression (Figure 6B)
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1–Induced Fibronectin Secretion1–induced fibronectin secretion by NRK-52E cells
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-SMA expression in a dose-dependent manner at day 4. H2O2 at concentrations of 100 µM and above significantly decreased E-cadherin expression (Figure 8C), and H2O2 at concentrations of 50 µM and above significantly increased -SMA expression (Figure 8D) compared with control. H2O2 at 100 µM did not increase Smad 2 phosphorylation up to 120 min (Figure 9A). H2O2 up to 500 µM did not affect Smad 2 phosphorylation at 30 min (data not shown)
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1–Induced Smad 2 Phosphorylation-SMA expression without significant effect on basal level (Figure 9C)
TGF-1–induced Smad2 phosphorylation was effectively inhibited by PD98059 but not by p38 MAPK inhibitor at doses that inhibited the effect of TGF-1 on E-cadherin and -SMA (Figure 10). p38 MAPK inhibitor up to 10 µM (twice the dose that inhibited the effect of TGF-1) did not inhibit TGF-1–induced Smad 2 phosphorylation
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1–Induced EMT in NRK-52E Cells1–induced EMT through both MAPK and Smad pathways
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Discussion |
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1–induced EMT (10). Although TGF-1 is known to signal through ROS (26–33), it is not known whether ROS are involved in TGF-1–induced renal tubular EMT. We hypothesized that ROS may play a role in TGF-1–induced EMT in renal tubular epithelial cells through activation of Smad or MAPK pathway
We confirmed in this study that TGF-1 activates Smad 2, p38 MAPK, and ERK1/2 and decreases E-cadherin and increases -SMA expression and fibronectin secretion by NRK-52E cells. We also confirmed that TGF-1 increases DCF-sensitive cellular ROS. Inhibition of NADPH oxidase and mitochondrial electron transfer chain subunit I as well as antioxidants significantly reduced, to similar extent, TGF-1–induced generation of cellular ROS, suggesting that NADPH oxidase and mitochondrial metabolism are important sources of TGF-1–induced cellular ROS. We previously demonstrated that TGF-1 upregulates NADPH oxidase subunit mRNA expression in LLC-PK1, another proximal tubular epithelial cell line (34). The effect of rotenone in this study is different from previous studies that demonstrated total inhibitory effect of DPI but not rotenone on TGF-1–induced ROS in rat hepatocyte (38) and human lung fibroblast (39). A slight but statistically significant increase in DHR-sensitive ROS (peroxinitrite) was observed after TGF-1 but not in dihydroethidine-sensitive ROS (superoxide anion; data not shown). This may be interpreted as a result of rapid conversion of superoxide anion to H2O2 by superoxide dismutase and even more rapid binding of superoxide to NO forming peroxinitrite
We (40) and others (41) have previously demonstrated that H2O2 upregulates TGF-1 mRNA and protein expression in glomerular mesangial cells and that antioxidants effectively inhibit high glucose–induced TGF-1 expression in mesangial cells (42) and diabetic kidneys (43). These observations together with the finding of this study that TGF-1 induces generation of cellular ROS (H2O2) suggest that ROS amplify TGF-1 signaling in renal cells
In this study, we found that antioxidants effectively reversed TGF-1–induced phosphorylation of Smad 2 and MAPK and the changes in E-cadherin and -SMA expression. Antioxidants, NADPH oxidase inhibitors, and an inhibitor of mitochondrial electron transfer chain subunit I all reduced TGF-1–induced DCF-sensitive cellular ROS, and NADPH oxidase inhibitors significantly reduced TGF-1–induced fibronectin secretion by NRK-52E cells. Exogenous H2O2 increased phosphorylated MAPK and induced EMT, strongly suggesting the role of ROS-MAPK in EMT. H2O2 failed to induce phosphorylation of Smad 2. Inhibition of ERK, however, effectively inhibited TGF-1–induced Smad 2 phosphorylation and H2O2-induced EMT, further suggesting the role of ROS-MAPK in EMT. A cross-talk between ERK and Smad has been known to exist in TGF-1 signaling (10,25). Elevated ERK activity can enhance Smad 2 activity, and ERK inhibition reduces TGF-1–stimulated Smad 2 phosphorylation (25). Our data are consistent with these earlier observations and provide a novel molecular signaling mechanism in which ROS-MAPK pathway mediates TGF-1–induced EMT in renal tubular epithelial cells. It seems that the effect of H2O2 on Smad phosphorylation varies in different cells. H2O2 increases Smad 2 phosphorylation in human diploid fibroblasts (44) but not in articular chondrocytes (45). In renal tubular epithelial cells, H2O2 failed to induce directly Smad 2 phosphorylation
Smad have been implicated in TGF-1–induced EMT (9,10,15,19), and our observations suggest that this could be, in part, through ROS-MAPK pathway. There is enough evidence that TGF-1 signals through MAPK. A microarray-based screen of transcriptional profiles of TGF-1–induced EMT in human keratinocytes revealed that ERK plays a role in TGF-1–directed cell motility and disruption of adherens junctions (19). ERK activation is also required in TGF-1–induced EMT in pancreatic cancer cells (20) and mammary epithelial cells (21). Activation of p38 MAPK is required in TGF-1–induced EMT in mammary epithelial cells (22) and in migration and proliferation of healing corneal epithelium (23). In agreement with these observations, our data also suggest that both p38 MAPK and ERK are required in TGF-1–induced EMT in NRK-52E cells. Both p38 MAPK inhibitor and MEK inhibitor effectively inhibited TGF-1- and H2O2-induced EMT. Inhibition of ERK but not p38 MAPK blocked TGF-1–induced Smad 2 phosphorylation. Our observation that antioxidants and ERK inhibitor (MEKi) prevented TGF-1–induced Smad 2 phosphorylation although exogenous H2O2 failed to induce directly Smad 2 phosphorylation suggest that ROS-MAPK pathway is also involved in EMT through Smad pathway
In conclusion, we demonstrated that ROS mediate TGF-1–induced EMT in renal tubular epithelial cells directly through activation of MAPK and indirectly through ERK-directed Smad 2 phosphorylation and suggest that antioxidants and MAPK inhibitors may prevent EMT through both MAPK and Smad pathways and subsequent tubulointerstitial fibrosis
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Acknowledgments |
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Y.Y. was a 2002 Asia-Pacific Economic Cooperation (APEC) postdoctoral fellow, supported by the Korea Science and Engineering Foundation (KOSEF)
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Footnotes |
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