The aqueous extract of lycopus lucidus turcz ameliorates streptozotocin-induced diabetic renal damage via inhibiting TGF-[beta]1 signaling pathway.
ARTICLE INFOKeywords:
TGF-[beta]
Lycopus lucidus
Smad
renal disease
ABSTRACT
Purpose Renal fibrosis characterized by accumulation of extracellular matrix protein results in chronic renal diseases including diabetic nephropathy. Transforming growth factor [beta]1 (TGF-[beta]1) signaling pathway plays a key role in mediating renal fibrosis. Hence, agents that antagonize TGF-[beta] signaling could be candidate for kidney disease therapy. Methods We established renal fibrosis model both in vitro with fibroblast cells treated with rhTGF-[beta]1 and streptozocin(STZ)-induced diabetic nephropathy rats model in vivo and evaluated the effect of the aqueous extract of Lycopus lucidus Turcz, the blood-circulation-promoting Chinese herb, on diabetic nephropathy and investigated the mechanism of action. Results We found that Lycopus suppressed rhTGF-[beta]1-induced Smad2 and ERK1/2 activation, down-regulated the expression of TGF-[beta]RI, TGF-[beta]RII, Smad4 and Smad7 in SV40 MES13 cells without inhibiting cell viability. In vivo, lycopus inhibited Smad2 phosphorylation, reduced mRNA level of TGF-[beta]1, ameliorated expansion of the mesangial area in glomerular tissue and reduced the levels of Scr and BUN of serum and total-SOD (superoxide dismutase) activity in STZ-induced diabetic rats. Conclusion Lycopus is a novel inhibitor of renal fibrosis by blocking TGF-[beta] signaling pathway and possess a protective effect on renal damage of STZ-induced diabetic nephropathy in rats.
[c] 2013 Elsevier GmbH. All rights reserved.
Introduction
Renal fibrosis characterized by accumulation of fibroblasts and excessive matrix proteins is the repair response of kidney for chronic injury and a major pathological feature of progressive kidney disease (Massague 1996; Eddy and Neilson 2006). Increasing evidences showed that TGF-[beta]1 is a key mediator in the pathogenesis of renal fibrosis(Bottinger 2007; Wang et al. 2005a). It is now well established that the binding of TGF-[beta] to its receptor Il (TGF-[beta]RII) activate the TGF-[beta] receptor typel (TGF-[beta]RI) kinase, resulting in phosphorylation of Smad2 and Smad3, subsequently, phosphorylated Smad2 and Smad3 bind to the common Smad4 and form the Smad complex, which translocates into the nucleus to regulate the target gene transcription (Kavsak et al. 2000).
Inhibition of TGF-[beta]1 pathway by suppression of TGF-[beta]1 expression(Isaka
et al. 1999) or blocking TGF-[beta]1action by neutralizing antibodies(Ma et al. 2004) attenuated renal fibrosis in animal models. However, these non-native approaches may produce unexpected results. Chinese herbal medicine has a long history in the treatment of kidney disease and some herbal medicine and extracts have proven to contain anti-fibrosis properties in vitro (Hu et al. 2009). Therefore, exploring natural, safe and effective antagonists of TGF-[beta]1 signaling pathway from Chinese herbal medicine has become an urgent issue for nephropathologists.
Lycopus lucidus Turcz, a kind of traditional Chinese medicine which can promote blood circulation and remove blood stasis(Tian et al. 2001) by inhibiting platelet aggregation and thombus formation(Shi et al. 2004). It has been reported that Lycopus can improve the symptoms of renal interstitial fibrosis in UUO rat model. However, the molecular mechanisms that Lycopus treat kidney disease need further to be revealed. In this study, we investigated the mechanism underlying the attenuation of renal fibrosis by Lycopus in interstitial fibroblast cells and the STZ-induced rat diabetic nephropathy model was also used to evaluate the effect of lycopus on suppression of diabetic nephropathy in vivo. Our findings will provide theoretical guidance to lycopus been used in the clinical treatment of diabetic nephropathy.
Materials and Methods
Lycopus extract preparation: the lycopus extract was prepared by Jiangsu Research Institute of Traditional Chinese Medicine. One hundred grams of the dried lycopus was immersed in 1000 ml of distilled water and boiled at 100 [degrees]C for 20 min. The particulate fraction was filtered using 325-mesh sieve, and the flow-through mixture concentrated to 100 ml at 40 C[degrees] and further lyophilized. The powder extract was stored at--80 [degrees]C and diluted as work concentration before use.
Cell lines: SV40 MES12 cell line was purchased from Chinese Academy of Sciences were maintained in DMEM medium (Invitrogen, Carlsbad, CA) supplemented with 15% fetal bovine serum (FBS) (Invitrogen, Carlsbad, CA). All cells were cultured in a humidified atmosphere with a 5% C[O.sub.2] incubator at 37 [degrees]C.
Antibodies: Recombinant human TGF-[beta]1, fibronectin, Smad4, pSmad2, Smad2, p-ERK1/2 and ERK1/2 antibodies were purchased from Cell Signaling Technology (Beverly, MA). TGF-[beta]RII, Smad7 and horseradish peroxidase-conjugated secondary antibodies were purchased from Santa Cruze (CA, USA). MTT (methyl thiazolyl tetrazolium) was purchased from Sigma-Aldrich (St Louis, MO, USA).
LC/MS Analysis
A LC/MS system (Waters, Milford, MA, USA) containing a Waters 2695 HPLC system, a Waters 996 photodiode array (PDA) detector, a Waters Quattro Micro tandem mass spectrometry with an electrospray ionization (ESI) source and a Waters Masslynx 4.0 software was used. Chromatographic separation was optimized in reference to the method of Wagner H. et al. (Wagner et al. 2011) at 35 Con an ODS column (150 x 4.6 mm i.d., 5 [micro]m; Hanbon, Nanjing, China). The mobile phase consisted of 0.1% acetic acid (I) and acetonitrile (II) at a flow rate of 1.0 ml/min. A gradient program was used as follows: 0 min, 5%II; 15 min, 30%II; 45 min, 100%II; 50 min, 100%II; 52 min, 5% II; 70 min, 5% II. The PDA detector scanned from 200 nm to 400 nm, the monitor wave length was set at 254 nm. The mass spectrometer was operated in the negative ESI mode using the selected ion recording data acquisition. Mass spectrometric conditions were optimized as follows: -3.0 kV capillary voltage, 120 [degrees]C source temperature, 400 [degrees]C desolvation temperature, 500 L/h desolvation gas flow, -30 cone voltage.
Cytotoxicity Assay
SV40 MES13 cells were incubated in triplicate in a 96-well plate at a density of 1 x [10.sup.4] cells with 100 [micro]l culture medium per well in the presence or absence of indicated concentrations (0, 100, 200, 400, 600, 800, 1000 [micro]/m1) of the lycopus extract for 24 h. 4 hours before the end of culture, 5 mg/ml MTT was added to each well, then the supernatant was aspirated and added 100 [micro]l of DMSO per well. The optical density of each well was measured in an ELISA microplate reader at 570 nm and 630 nm wavelengths.
Western blot assay
To detect the effects of lycopus extract on TGF-[beta]1-induced TGF-[beta] receptors, Smad4 and Smad7 expression, SV40 MES13 cells were treated with various concentrations (0 [micro]g/ml, 50[micro]g/ml, 100 [micro]g/ml, 200 [micro]g/ml, 400 [micro]) of lycopus extract for 24 h before stimulated with 10 ng/ml of TGF-[beta]1 for 30 min, After which whole-cell extracts were processed for western blot analysis using anti-TGF-[beta]RI, anti-TGF-[beta]RII, anti-Smad4 and anti-Smal7 antibodies. To detect the effects of lycopus extract on TGF-[beta]1-induced Sma12 and ERK1/2 phosphorylation in SV40 MES13 cells, SV40 MES13 cells were stimulated with 10 ng/ml of TGF-[beta]1 for various length of time (0 min, 15 min, 30 min, 45 min, 60 min, 120 min), After which whole-cell extracts were processed for western blot analysis using anti-pSmad2, anti-Smad2, anti-pERK1/2 and anti-ERK1/2 antibodies, GAPDH served as a loading control. The cells with different treatments were harvested, washed twice in PBS and lysal for 5 min at 4 [degrees]C with ice cold RIPA buffer (1% NP-40 in 150 mM NaCl, 50 mM Tris base, 2 mM EDTA). Equalized amounts of proteins from each sample were subjected to SDS-PAGE, protein bands were transferred to PVDF membranes and then the PVDF membranes were blocked in 1% (w/v) BSA for 2h, and the blots were probed with a 1:1000 (w/v) dilution of primary antibody overnight at 4 [degrees]C. After washing, the blots were probed with secondary antibody conjugated with IgG horseradish peroxidase (HRP) for 1 h at room temperature, washed in TBST for three times, immune complexes were detected by the enhanced chemiluminescence system. GAPDH was used as the loading control.
Reverse-Transcription Polymerase Chain Reaction (RT-PCR)
Total RNA was extracted from the glomerular tissue collected from each group using trizol reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's protocol and then RNA was converted to cDNA by reverse transcriptase (Transgene, China) according to the manufacturer's instruction. The relative expression of TGF-[beta]1 was analyzed using reverse-transcription polymerase chain reaction (RT-PCR) with GAPDH as an internal control. The RT-PCR reaction was processed according to previous described (Kunnumakkara et al. 2009). The following primers were used for identification: TGF-[beta]1 (sense: 5'-CCTGCTGCTTTCTCCCTCAACC-3', antisense: 3'- CTGGCACTGCTTCCCGAATGTC-5'), GAPDH(sense: 5'-GTGGACATTGTTGCCATCAACG-3, antisense: 3'-GAGGGAGTTGTCATATTTCTCG-5'). The PCR products were detected by 1.0% agarose gel electrophoresis and photographed.
Measurement of uric protein and blood biochemical parameters
Uric protein and blood biochemical parameters were measured using commercial available kits (Jianchen, institute of Biotechnology, Nanjing, China).
Histological examination
The kidney was fixed in 10% phosphate-buffered formalin solution, and embedded in paraffin. Sections of 4 [micro]m thickness were cut and stained with Periodic acid-Shiff base (PAS) and Sirius red (0.5% solution in saturated aqueous picric acid) (Polysciences, Inc., Warrington, PA, USA)
In vivo experimental design
45 Sprague-Dawley male rats, weighing (g) (SPF, Certificate No. SCXK (Jiang su) 2009. 001, were purchased from Shanghai SLAC Experiment Animal Limited Company. All animals were housed in an air-conditioned room at 23 [+ or -] 1 [degrees]C with a 12 h light/dark cycle and allowed ad libitum access to water and standard pelleted diet containing 18% protein (w/w). After 1 week acclimatization, the rats were injected STZ (Sigma, China, 50 mg/kg body weight) to induce diabetes model. After 48h injection, the rats showing hyperglycemia (> 16.7 mM) were randomly assigned to five groups (9 animals in each group): normal group, STZ model group, STZ + Lycopus (3 g/kg) group and STZ + Lycopus (6 g/kg) group and STZ + Lycopus (12 g/kg) group. Rats were sacrificed after 30 days treatment and the kidneys were removed. A portion of each kidney was fixed in 10% phosphate-buffered formalin for histological and immunohistochemical studies after paraffin embedding. The remainder was snap-frozen in liquid nitrogen and stored at 80 [degrees]C for hypcontent determination and protein extractions. All experimental procedures were carried out in accordance with NIH (Guide for the Care and Use of Laboratory Animals, 1996) during the study.
Statistic Analysis
Three or more separates experiments were performed. Statistical differences were analyzed by Student's T-test or one way analysis of variance with post hoc Dunnett's T 3. All statistical analysis were processed by SPSS 13 software. P < 0.05 was considered statistically significant.
Results
The composition analysis of lycopus aqueous extract
A LC/MS system was developed for detection the main compounds in lycopus aqueous extract. As shown in Fig. 1 and Table 1, the main compounds in lycopus aqueous extract are caffeic acid, luteolin-7-O-[beta]-D-glucoside and rosmarinic acid.
Table 1 Characterization of compounds in lycopus extracts by LC/MS. Peak no. Rt (tR, min) Compound name 1 8.5 Calffeic acid 2 11.6 Luteolin-7-O-[beta]-D-glucoside 3 13.4 Rosmarinic acid Peak no. Molecular formula Molecular weight 1 [C.sub.9] [H.sub.8] [O.sub.4] 180 2 [C.sub.21] [H.sub.20] [O.sub.11] 448 3 [C.sub.18] [H.sub.16] [O.sub.8] 359
Effects of lycopus on SV40 MES cell cytotoxicity
Lycopus is used as a traditional Chinese medicine. We investigated the effects of lycopus on SV40 MES cell cytotoxicity, As shown in Fig. 2, each concentration of lycopus extract induced SV40 MES cell proliferation significantly (p <0.05) except the concentration of 1000 [micro]g/ ml.
Lycopus inhibited TGF-[beta]1-induced Smad2 and ERK1/2 phosphorylation
Whether lycopus affect TGF-[beta]1-induced Smad2 activation was investigated, TGF-[beta]1 induced Smad2 activation significantly and the lycopus extract inhibited TGF-[beta]1-induced Smad2 phosphorylation in a dose-dependent manner whereas exert no inhibitory effect on total Smad2 (Fig. 3 A, B).
Whether lycopus extract affect ERK1/2 phosphorylation was also evaluated. As shown in Fig. 3 C, D, lycopus extract significantly inhibited ERK1/2 phosphorylation, while total ERK1/2 was not affected by lycopus extract treatment.
Effects of lycopus on the expression of Smad4 and Smad7
Smad family is the most important mediator for post-receptor signaling of TGF-[beta], whether other Smads-related signal moleculars could be affected by lycopus extract were also investigated. The results showed that TGF-[beta]1 significantly increased the expression of Smad 4. Conversely, lycopus extract treatment dramatically suppressed TGF-[beta]1-induced upregulation of Smad 4 and Smad 7 expression in a dose-dependent manner (Fig. 4).
Lycopus reduced the protein expression of TGF-[beta]RI and TGF-[beta]RII
Binding of TGF-[beta] to its type II receptor starts the interaction of a complex chain of signaling molecules, and finally leads to TGF-[beta]-induced gene transcription. To determine which part of TGF-[beta] signaling was changed by lycopus extract. We investigated the protein expression of TGF-receptor I and TGF-receptor II after lyco-pus extract treatment. The results showed that the protein level of TGF-[beta]RII was increased by TGF-[beta] stimulation and lycopus extact inhibited this up-regulation effect in a dose-dependent manner (Fig. 5 A, C) whereas the protein level of TGF-[beta]RI was unchanged after lycopus extract treatment (Fig. 5 A, B).
Effects of lycopus on glomerular changes
Histological examination of the kidneys through light microscope showed that increased inflammatory cell infiltration and extracellular matrix accumulation in renal tubular interstitial region induced by STZ. After 30 days treatment with different doses of lycopus extract, glomerular hypertrophy and mesangial matrix accumulation induced by STZ were inhibited compared with that of STZ model group (Fig. 6).
Lycopus extract suppressed mRNA level of TGF-[beta]1 in glomerular tissue of STZ model rats
RT-PCR analysis was used to investigate whether lycopus extract affect mRNA level of TGF-[beta]1 in glomerular. As shown in Fig. 7 A, the mRNA level of TGF-[beta]1 was significantly increased in STZ model group rats whereas lycopus extract treatment reduced TGF-[beta]1 expression in glomerular tissue of STZ-induced diabetic rats in a dose-dependent manner.
Lycopus extract treatment inhibited Simad2 phosphorylation in glomerular tissue of STZ model rats
Lycopus extracts inhibited TGF-[beta]1-induced Smad2 phosphorylation in glomerular mesangial cells and suppressed gene expression of TGF-[beta]1 in lycopus treated STZ rat glomerular. Whether lycopus extract could inhibit Smad 2 activation in glomerular tissue was also investigated. Smad 2 phosphorylation in glomerular of lycopus extract treated STZ rats was suppressed comparing with that in glomerular of normal and STZ model rats (Fig. 7 B, C).
Changes in renal function related parameters
Renal function related parameters were determined during the study period. As shown in Table 2, at the termination of 30-days treatment, the urine volume and urine protein of STZ-diabetic group were significant higher than those of non-diabetic group. However, lycopus treatment significantly reduced the urine volume and urine protein in STZ-diabetic rats comparing with STZ-diabetic model group. The levels of serum Cr (Serum creatine) and BUN (blood urea nitrogen) in STZ-diabetic model group were higher than those of non-diabetic group, after receiving lycopus (12 mg/kg) for 30 clays, STZ-induced diabetic rats showed a decreased levels of serum Cr and BUN. In addition, STZ-induced diabetic rats showed a increase of the activity of total-SOD after receiving lycopus for 30 clays.
Table 2
Changes of general condition of each group.
Group 30 days
Urine volume Control 9.44 [+ or -] 3.48
(a)
STZ 58.92 [+ or -] 24.12
(a)
STZ + Lycopus (3) 55.00 [+ or -] 16.97
(a)
STZ + Lycopus (6) 60.10 [+ or -] 32.37
(a)
STZ + Lycopus (12) 56.81 [+ or -] 22.53
(a)
Urine protein (mg/24 h) Control 3.61 [+ or -] 0.896
(a)
STZ 29.92 [+ or -] 6.06
STZ+ Lycopus (3) 14.75 [+ or -] 6.96
(a)
STZ + Lycopus (6) 14.55 [+ or -] 4.82
(a)
STZ + Lycopus (12) 13.14 [+ or -] 3.69
(a)
Serum Cr([micro]M) Control 40.10 [+ or -] 9.18
(a)
STZ 88.67 [+ or -] 13.58
STZ + Lycopus (3) 67.00 [+ or -] 10.71
STZ + Lycopus (6) 62.21 [+ or -] 24.66
STZ + Lycopus(12) 65.95 [+ or -] 14.67
(a)
BUN (mM) Control 4.87 [+ or -] 1.72
(a)
STZ 13.56 [+ or -] 3.53
STZ + Lycopus (3) 12.80 [+ or -] 1.49
STZ + Lycopus (6) 11.69 [+ or -] 4.81
STZ + Lycopus (12) 10.58 [+ or -] 1.90
(a)
SOD(U/ml) Control 111.12 [+ or -] 7.68
(a)
STZ 101.01 [+ or -] 5.40
STZ + Lycopus (3) 119.40 [+ or -] 2.79
(a)
STZ + Lycopus (6) 115.65 [+ or -] 8.48
(a)
STZ + Lycopus (12) 115.58 [+ or -] 3.87
(a)
(a) P<0.05, compared to the values of STZ group (n>9)
Discussion
In this study, we firstly found that lycopus own potential to treat diabetic renal disease. It is now well accepted that Smad2 and Smad3 are two critical downstream mediators responsible for the biological effects of TGF-[beta]1(Lan 2011), Smad4 also play a key role in TGF-[beta]1 signaling pathway. Smad2 and Smad3 are strongly activated in both experimental and human kidney diseases, including diabetic nephropathy (Li et al. 2004). We found that lycopus treatment inhibited TGF-[beta]1-induced Smad 2 phosphorylation in SV40 MES cells. Upregulation of TGF-[beta]1 has been found in experimental animal model, this is agreement with our result that TGF-[beta]1 is upregulated in STZ-induced diabetic rats. Lycopus treatment significantly reduced the overexpression of TGF-[beta]1 in glomerular tissue of STZ-induced diabetic rats and it consistent with significantly decrease of the phosphorylation of Smad2. The expression of Smad4 and T[beta]RII protein also were suppressed by lycopus in SV40 MES cells. The above results indicated that the attenuation effect of lycopus on diabetic renal disease is associated with the suppression of TGF-[beta]1 signaling. Many other mediators can activate Sma12 and Smad3 independent from TGF-[beta]1 because Smads act as signal integrators and interact with other signaling pathways, mitogen-activated protein kinase (MAPK) signaling pathway also play a role in the pathological processes of kidney diseases(Wang et al. 2005b; Lan and Chung 2011). Smad7 is an inhibitory Smad that negatively regulates Smad2 and Smad3 activation and functions by targeting the TGF-[beta]RI and Smads for degradation via the ubiquitin protea-some degradation mechanism (Kavsak et al. 2000; Ebisawa et al. 2001). In this study, we found that lycopus decreased the expression of Smad 7, in contrast to our results, Yu-Lin Yang found that a novel renal fibrosis antagonist safflower extract up-regulated the protein level of Smad7 (Yang et al. 2008). It indicated that lycopus inhibited TGF-[beta]1 pathway not via up-regulating Smad7 expression.
TGF-[beta]1 is a potent stimulus of extracellular matrix expression that has been correlated clinically and in experimental models with diabetic nephropathy (Sharma and McGowan 2000; lwase et al. 1994). Diabetic nephropathy is characterized by hypertrophy of both glomerular and tubulat element, which lead to glomerulosclerosis and tubulointerstitial fibrosis by increasing synthesis and accumulation of extracellular matrix(Kawada et al. 1999). Inhibition of TGF-[beta]1 significantly reduced renal fibrosis and decreased the mRNA levels of key mediators of extracellular matrix deposition in the kidneys of db/db mouse (Petersen et al. 2008). Lycopus treatment significantly inhibited the glomerular mesangial matrix accumulation in glomerular tissue of STZ-induced diabetic rats.
The above findings were further confirmed by in vivo biochemical results from STZ-induced diabetic rats. In STZ-induced diabetic nephropathy rat model, the kidney is characterized by increased fibrosis and decreased renal function. The index (urine protein, Serum Cr, BUN and SOD) correlated with renal function indicated that lycopus treatment significantly ameliorate the symptom of decreased renal function in STZ-induced diabetic rats. Urine protein, measuring of the severity and determinant for diabetic renal disease progression, is recognized as a clinical signature, as well as a risk factor of renal lesions in diabetic nephropathy(Parving 2001). Our result found that lycopus-administration significantly inhibited the STZ-induced increase of urine protein.
Accumulated evidence has demonstrated that kidney fibrosis is involved in (reactive oxygen species, ROS)/oxidatic stress (Kawada et al. 1999; Docherty et al. 2006). Inhibition of ROS stress by activation of scavenging enzymes and treatment with scavenging reagents attenuated kidney fibrosis (Chan et al. 1998). In agreement with previous study, in our study, the activity of SOD in STZ-induced diabetic rats decreased significantly. Lycopus administration significantly inhibited the STZ-induced decreased of SOD activity, it indicated that the effect of lycopus is also associated with the reduction of oxidative stress.
Conclusions
In summary, lycopus exerts an inhibitory effect on TGF-[beta]1 signaling pathway in SV40 MES cells and in STZ-induced diabetic rats model via suppressing TGF-[beta]1 expression, inhibiting the protein level of TGF-[beta]RI, Smad4 and Smad2 phosphorylation and further improving the renal function of diabetes rats by increasing SOD activity and reducing urine protein. These results demonstrated that lycopus has potential for amelioration of diabetic nephropathy via blockade of TGF-[beta]1 pathway.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos.81274150, Nos.81202967) and Jiangsu Province's Outstanding Leader Program of Traditional Chinese Medicine.
* Corresponding author at: Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Traditional Chinese Medicine, 100#, Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China. Tel.: +86 25 85608666: fax: +86 25 85608666.
E-mail address: pcao79@yahoo.com (P. Cao).
0944-7113/$--see front matter [c] 2013 Elsevier GmbH. All rights reserved.
http://dx.doi.org/10.1016/j.phymed.2013.06.004
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Yuanzhang Yao (a), Jie Yang (a), Dawei Wang (a), Fei Zhou (a), Xueting Cai (a), Wuguang Lu (a), Chunping Hu (a), Zhenghua Gu (a), Shihui Qian (b), Xiaoxiang Guan (b), Peng Cao (a), *
(a) Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China
(b) Department of Medical Oncology, jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China
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| Title Annotation: | transforming growth factor beta 1 |
|---|---|
| Author: | Yao, Yuanzhang; Yang, Jie; Wang, Dawei; Zhou, Fei; Cai, Xueting; Lu, Wuguang; Hu, Chunping; Gu, Zhen |
| Publication: | Phytomedicine: International Journal of Phytotherapy & Phytopharmacology |
| Article Type: | Report |
| Geographic Code: | 9CHIN |
| Date: | Oct 15, 2013 |
| Words: | 4525 |
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