Tanshinone IIA improves diabetes mellitus via the NF‑κB‑induced AMPK signal pathway

  • Authors:
    • Feng‑Yi Yuan
    • Min Zhang
    • Ping Xu
    • Dan Xu
    • Ping Chen
    • Min Ren
    • Qin Sun
    • Jing‑Yan Chen
    • Juan Du
    • Xia‑Lian Tang
  • View Affiliations

  • Published online on: September 3, 2018     https://doi.org/10.3892/etm.2018.6674
  • Pages: 4225-4231
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Abstract

Diabetes mellitus (DM) is a systemic metabolic disease. Tanshinone IIA (Tan‑IIA) presents potential benefits for DM. The purpose of this study was to investigate the efficacy of Tan‑IIA in type 2 DM rats and explore its potential mechanism in renal cells. A type 2 DM rat model was established and administered with Tan‑IIA or PBS. It was demonstrated that Tan‑IIA treatment significantly reduced levels of total cholesterol, non‑esterified fatty acids, total triglyceride and low‑density lipoprotein cholesterol in experimental DM rats compared with the control group. The results indicated that Tan‑IIA treatment significantly decreased levels of interleukin (IL)‑8, tumor necrosis factor‑α, C‑reactive protein and IL‑6. It was identified that Tan‑IIA treatment significantly decreased nuclear factor‑κB levels and significantly elevated 5' adenosine monophosphate‑activated protein kinase levels. Western blot analysis indicated that Tan‑IIA elevated immunocyte precipitation in renal cells. Furthermore, Tan‑IIA treatment improved lipid metabolism, glucose metabolism, insulin resistance and body weight of type 2 DM rats. In conclusion, Tan‑IIA administration may inhibit inflammatory cytokines and alleviate type 2 DM symptoms in experimental rats.

Introduction

Diabetes mellitus (DM) is a metabolic disease that is characterized by insulin secretion defects (1,2). DM is also an heterogeneous disease, which can be classified into type 1 and type 2 DM (3). Diabetic cardiomyopathy is often caused by metabolic disorders and microvascular lesions in patients with DM, and diabetic cardiomyopathy is responsible for inflammation and apoptosis of myocardial tissue (24). Diabetic cardiomyopathy is a major risk factor for the development of insulin resistance in patients with DM (5). The occurrence of hyperglycemia and metabolic syndrome may lead to the initiation and development of diabetic cardiomyopathy in patients with DM (6). These metabolic imbalances induced by diabetic cardiomyopathy may result in disturbed metabolism (7). Therefore, it is essential to understand the potential mechanism of DM to treat DM-induced metabolic syndrome in patients.

Tanshinone IIA (Tan-IIA) is a traditional Chinese medicine, which is extracted from Danshen (Salvia miltiorrhiza) and has been clinically used for the treatment of human cardiovascular and inflammatory diseases (8,9). A previous study demonstrated that Tan-IIA can inhibit human cancer cell growth, and affects cell cycle regulation, cell proliferation, apoptosis and DNA synthesis (10). In addition, Tan-IIA significantly reduces lipopolysaccharide-induced acute lung injury by inhibiting inflammation and apoptosis in mice (11). Furthermore, renal fibrosis and inflammation can be attenuated by Tan-IIA via altering the expression of transforming growth factor-β/Smad and nuclear factor (NF)-κB signaling pathways in nephrectomized rats (12). Notably, Tan-IIA may serve a protective function against renal damage in type 2 DM through improving renal function, which could be a new evidence-based therapy for diabetic nephropathy (13).

In the present study, based on the link between inflammation and DM, it was assumed that Tan-IIA may have beneficial effects on type 2 DM rats. The potential mechanisms mediated by Tan-IIA were investigated in a type 2 DM rat model. To the best of our knowledge, this is the first study to demonstrate that Tan-IIA inhibits inflammation and alleviates type 2 DM symptoms through NF-κB-induced 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling in experimental rats.

Materials and methods

Ethics statement

The protocols were approved by the Ethics Committee of Sichuan Province People's Hospital and Sichuan Academy of Medical Sciences (Chengdu, China). Anesthesia was administered using intravenous sodium pentobarbital (35 mg/kg, Sigma-Aldrich; Merck KGaA, Darmstadt, Germany).

Animal model

A total of 20 male Sprague-Dawley (SD) rats (age, 6–8 weeks; body weight, 320–340 g) were purchased from Charles River Laboratories (Beijing, China). All rats were housed in a temperature-controlled room (25±1°C) with a 12-h light/dark cycle. All rats were given accessed to food and water ad libitum. Type 2 DM was induced in SD rats (n=20) using streptozotocin and high-fat diet, as described previously (14). The experimental rats with type 2 DM were then divided into two groups (n=10 in each) and received Tan-IIA (10 mg/kg; Sigma-Aldrich; Merck KGaA) or PBS (10 mg/kg, 120 µl) by intragastric administration once every 2 days. Healthy male SD rats (n=10; age, 6–8 weeks; body weight, 320–340 g; Beijing University, Beijing, China) that did not receive treatment were used as controls and kept under the same conditions as the experimental rats. The treatments were continued for 8 weeks, and kidney weight (KW) and body weight (BW) were measured at the end of week 8. Total cholesterol (TC), non-esterified fatty acids (NEFAs), total triglyceride (TG) and total low density lipoprotein cholesterol (LDL-C) were measured at the end of week 8 as described previously (15).

Insulin tolerance tests

Experimental rats were fasted for 6 h after 8 weeks of treatment with Tan-IIA or PBS. Type 2 DM rats were injected with insulin (Sigma-Aldrich; Merck KGaA) intraperitoneally at 0.75 U/kg body weight. Blood glucose levels were measured 40 min after the insulin injection using a blood glucometer (Changsha Sannuo Biological Sensing Technology Co., Ltd., Changsha, China).

ELISA

Serum was isolated from 3 ml peripheral blood using centrifugation at 4,000 × g for 15 min at 4°C. The concentrations of serum parameters were analyzed following treatment to identify mice in which chronic renal failure was induced by type 2 DM. ELISA kits were used to determine interleukin (IL)-6 (M6000B; R&D Systems, Inc., Minneapolis, MN, USA), IL-10 (DY417; R&D Systems, Inc.), C-reactive protein (CRP; MCRP00; R&D Systems, Inc.), tumor necrosis factor (TNF)-α (MTA00B; R&D Systems, Inc.), blood urea nitrogen (BUN; MBUN002; R&D Systems, Inc.) and creatinine serum levels (KGR005; R&D Systems, Inc.) in rats. The procedures were performed according to the manufacturer's protocols. The final results were recorded at 450 nm on an ELISA plate reader (Bio-Rad Laboratories, Inc., Hercules, CA, USA).

Western blot analysis

Rats were sacrificed and renal tissues were isolated from rats as described previously (16) for further analysis at the end of week 8. Renal cells were homogenized in 1X radioimmunoprecipitation assay buffer (Sigma-Aldrich; Merck KGaA) and western blotting was performed to analyze the protein expression. Briefly, protein concentrations were examined using a BCA protein assay (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA) and protein samples (40 µg) were separated by 15% SDS-PAGE. Proteins were then blotted on a nitrocellulose membrane and blocked with 5% skimmed milk for 1 h at 37°C. Membranes were incubated with primary antibodies against AMPK (1:2,000; cat. no. ab32047; Abcam, Cambridge, MA, USA), NF-κB p65 (1:2,000; cat. no. ab16502; Abcam), IL-6 (1:2,000; cat. no. ab9324; Abcam), IL-10 (1:2,000; cat. no. ab33471; Abcam), TNF-α (1:1,000; cat. no. ab6671; Abcam), CRP (1:2,000; cat. no. ab70010; Abcam), insulin receptor substrate (IRS)-1 (1:2,000; cat. no. ab52167; Abcam) and β-actin (1:2,000, cat. no. ab8226; Abcam) for 12 h at 4°C. Membranes were then incubated with horseradish peroxidase-conjugated goat anti-rabbit IgG mAb (1:5,000; PV-6001; OriGene Technologies, Inc., Beijing, China) for 2 h at 37°C. The blots were visualized using a chemiluminescence detection system (Invitrogen; Thermo Fisher Scientific, Inc.). All the experiments were performed in triplicate. Densitometric quantification of the immunoblot data was performed by Quantity-One software (version 2.0; Bio-Rad Laboratories, Inc.).

NF-κB overexpression

Renal cells (1×105) were isolated from experimental type 2 DM rats before treatments as described previously (17) and were cultured in in RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS; both Thermo Fisher Scientific, Inc.) in 6-well plates for 12 h at 37°C until 85% confluence. The media was then removed from the culture plate, followed by three PBS washes. Renal cells were transfected with 100 pmol lentivirus-NF-κB (pNF-κB) or lentivirus-vector (pControl; both Invitrogen; Thermo Fisher Scientific, Inc.) using Lipofectamine 2000 (Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol. NF-κB-overexpressed renal cells were used for further analysis following transfection for 48 h at 37°C.

Immunohistochemical analysis

Renal tissues were obtained at week 8 and fixed in 10% formaldehyde for 2 h at 37°C. Paraffin-embedded renal tissue sections (4-µm-thick) were prepared and epitope retrieval was performed using water-bath heating for further analysis (18). Following dehydration in graded ethanol (100, 95 and 85%) and xylene, tissue sections were deparaffinized in xylene, rehydrated in descending ethanol series, followed by blocking of endogenous peroxidase activity in 3% hydrogen peroxide for 10 min at 37°C. The paraffin sections were treated with hydrogen peroxide (3%) for 15 min and subsequently were blocked with 5% bovine serum albumin (Sigma-Aldrich; Merck KGaA) for 30 min at 37°C. The tissue sections were incubated with rabbit anti-mouse CD3 (1:1,000; cat. no. ab1669, Abcam) and CD19 (1:1,000; cat. no. ab25232, Abcam) at 4°C for 12 h. Sections were then incubated with an Alexa 488-labeled goat anti-rabbit IgG antibody (cat. no. A-11034; 1:400; Molecular Probes; Thermo Fisher Scientific, Inc.) at 37°C for 2 h. Stained sections were examined using an inverted laser scanning microscope (LSM 410; Zeiss AG, Oberkochen, Germany). The semi-quantification of immunoreactivity on each slide was evaluated using ImageJ software (version 1.02; National Institutes of Health, Bethesda, MD, USA).

Statistical analysis

Data are expressed as the mean ± standard error of mean. All data were analyzed using SPSS version 16.0 (SPSS, Inc., Chicago, IL, USA). Groups were compared using one-way analysis of variance followed by a Student-Newman-Keuls test. P<0.05 was considered to indicate a statistically significant difference.

Results

Tan-IIA treatment improves glucose metabolism and insulin resistance in type 2 DM rats

As indicated in Fig. 1A-C, Tan-IIA treatment significantly decreased blood glucose and serum levels of BUN and creatinine in type 2 DM rats compared with the control group (P<0.01). Tan-IIA treatment significantly improved insulin resistance for type 2 DM rats compared with the control group (Fig. 1D; P<0.01 at 40 min, P<0.05 at 80 and 120 min). Notably, compared with the control, Tan-IIA treatment resulted in higher KW (Fig. 1E; P<0.01) and BW (Fig. 1F; P<0.05). These results suggested that Tan-IIA treatment is beneficial for the improvement of glucose metabolism and insulin resistance in type 2 DM rats.

Tan-IIA treatment improves lipid metabolism for type 2 DM rats

As indicated in Fig. 2, it was observed that Tan-IIA treatment significantly reduced serum levels of TC, NEFAs, TG and total LDL-C in type 2 DM rats compared with the control group (P<0.01). These results suggested that Tan-IIA treatment is beneficial for improving lipid metabolism in type 2 DM rats.

Tan-IIA decreases inflammation in type 2 DM rats

As indicated in Fig. 3, it was demonstrated that Tan-IIA treatment significantly decreased levels of IL-8 (P<0.01), TNF-α (P<0.05), CRP (P<0.01) and IL-6 (P<0.05) compared with the control group. These results suggested that Tan-IIA treatment decreases inflammation in type 2 DM rats.

Tan-IIA treatment reduces inflammation via the NF-κB-induced AMPK signaling pathway

The possible mechanism of Tan-IIA in renal cells in type 2 DM was investigated. The results identified that Tan-IIA treatment significantly decreased expression levels of NF-κB p65 (P<0.05; Fig. 4A) and significantly elevated AMPK expression levels in renal cells (P<0.01; Fig. 4A). Western blot analysis also indicated that Tan-IIA significantly elevated expression levels of IRS-1 (P<0.01; Fig. 4B) and significantly decreased immunocyte precipitation in renal cells (P<0.01; Fig. 4C). Western blotting indicated that NF-κB overexpression (pNF-κB) increased NF-kB p65 expression compared with the control and abolished Tan-IIA-increased AMPK levels in renal cells (both P<0.01; Fig. 4D). NF-κB overexpression also increased and blocked Tan-IIA-inhibited IL-8, TNF-α, CRP and IL-6 in renal cells isolated from rats (all P<0.01; Fig. 4E). These results suggested that Tan-IIA treatment reduces inflammation via an NF-κB-induced AMPK signaling pathway in renal cells of a type 2 DM rat model.

Discussion

DM can lead to upregulation of inflammatory cytokines, which results in metabolic syndrome (19). A previous study described a novel mechanism for Tan-IIA in regulating vasorelaxation and may help to better understand the cardiovascular protective action of Tan-IIA (20). In the present study, the beneficial effects of Tan-IIA treatment for DM rats were investigated in vitro and in vivo. A dose of 10 mg/kg was used to evaluate the efficacy of Tan-IIA for DM, as described previously (21). The present findings indicated that Tan-IIA administration could decrease inflammatory cytokines, and alleviate glucose intolerance and insulin resistance in experimental rats. The current study also identified that Tan-IIA could improve insulin resistance in type 2 DM mice via the NF-κB-induced AMPK signaling pathway.

Inflammation is regarded as a central pathophysiological process in the development of type 2 DM (22). A previous study demonstrated that circulating IL-8 is associated with reduced insulin-like growth factor 1 and poor metabolism in adolescents with DM (23). A systematic review and meta-analysis indicated that serum TNF-α levels are upregulated in type 2 DM patients, which is regarded as an elevated inflammatory burden in type 2 DM patients (24). In addition, CRP is a biomarker for patients with DM (25). Furthermore, a previous study revealed that IL-6 levels are higher in patients with type 2 DM compared with healthy individuals (26). In the present study, it was observed that Tan-IIA treatment significantly decreased inflammatory factors TNF-α, IL-6, CRP and Il-8 in a type 2 DM rat model. However, long-term experiments are required to verify these findings.

DM significantly affects blood glucose levels due to insufficient insulin concentration (27). It was observed in the current study that Tan-IIA treatment decreased blood glucose and reduced insulin resistance in DM rats. A previous report identified that serum levels of BUN and creatinine are higher in DM patients compared with healthy individuals (28). In the present study, it was demonstrated that Tan-IIA downregulated serum levels of BUN and creatinine, and increased KW and BW for type 2 DM rats. Additionally, lipid metabolism disorder frequently occurs in DM patients (29). It was observed that Tan-IIA treatment significantly reduced TC, NEFAs, TG and LDL-C compared with the control group in type 2 DM rats.

NF-κB is involved in inflammation and insulin resistance in adipose cells in type 2 DM, and contributes to inhibition of inflammation and improves insulin resistance (30). In the present study, it was observed that NF-κB expression levels were increased in type 2 DM rats and downregulated by Tan-IIA treatment. A previous report demonstrated that targeting of the IRS-1 pathway may regulate insulin resistance in type 2 DM rats (31). In the present study, Tan-IIA elevated expression levels of IRS-1 in renal cells in type 2 DM rats. Upregulation of AMPK levels following Tan-IIA treatment was first reported in renal cells, and may further reduce production and activity of glucose-6-phosphatase in type 2 DM rats (32). However, a limitation of the present study was that only the number of immunocytes and expression of inflammatory cytokine levels were measured in renal cells. Further studies should be performed to analyze immunocytes and inflammatory cytokine expression in liver or adipose tissues in type 2 DM.

In conclusion, the present study indicates that Tan-IIA may have beneficial effects for treating type 2 DM rats. The findings suggest that Tan-IIA treatment improves type 2 DM via regulation of the NF-κB-induced AMPK signaling pathway. However, further studies are required to identify the efficacy of Tan-IIA in patients with type 2 DM.

Acknowledgements

Not applicable.

Funding

The present study was supported by Cadre Health Care Program of Sichuan Province as part of the following study, ‘Study on the role of islet alfa cell function in the initiation and development of type 2 diabetes mellitus and the mechanisms of related drug intervention’ (grant no. 2012–202, 30305030325).

Availability of data and materials

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Authors' contributions

FYY performed the experiments. MZ designed the experiments. PX, DX, PC, MR, QS, JYS, JD and XLT prepared the investigations and analyzed data.

Ethics approval and consent to participate

The protocols were approved by the Ethics Committee of Sichuan Province People's Hospital & Sichuan Academy of Medical Sciences (Chengdu, China).

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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November-2018
Volume 16 Issue 5

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Spandidos Publications style
Yuan FY, Zhang M, Xu P, Xu D, Chen P, Ren M, Sun Q, Chen JY, Du J, Tang XL, Tang XL, et al: Tanshinone IIA improves diabetes mellitus via the NF‑κB‑induced AMPK signal pathway. Exp Ther Med 16: 4225-4231, 2018
APA
Yuan, F., Zhang, M., Xu, P., Xu, D., Chen, P., Ren, M. ... Tang, X. (2018). Tanshinone IIA improves diabetes mellitus via the NF‑κB‑induced AMPK signal pathway. Experimental and Therapeutic Medicine, 16, 4225-4231. https://doi.org/10.3892/etm.2018.6674
MLA
Yuan, F., Zhang, M., Xu, P., Xu, D., Chen, P., Ren, M., Sun, Q., Chen, J., Du, J., Tang, X."Tanshinone IIA improves diabetes mellitus via the NF‑κB‑induced AMPK signal pathway". Experimental and Therapeutic Medicine 16.5 (2018): 4225-4231.
Chicago
Yuan, F., Zhang, M., Xu, P., Xu, D., Chen, P., Ren, M., Sun, Q., Chen, J., Du, J., Tang, X."Tanshinone IIA improves diabetes mellitus via the NF‑κB‑induced AMPK signal pathway". Experimental and Therapeutic Medicine 16, no. 5 (2018): 4225-4231. https://doi.org/10.3892/etm.2018.6674