Atorvastatin prevents glomerular extracellular matrix formation by interfering with the PKC signaling pathway
- Authors:
- Published online on: March 9, 2018 https://doi.org/10.3892/mmr.2018.8724
- Pages: 6441-6448
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Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Diabetic neuropathy (DN) is an important microvascular complication of diabetes. The principal pathological alterations in DN include hypertrophic mesangial cells (MCs), the abnormal deposition of the extracellular matrix (ECM) and renal interstitial fibrosis (1). Fibronectin (Fn) is an important component of the ECM. Fn is primarily synthesized in the early stages of DN and is associated with the local inflammatory reaction of the kidney (2). Collagen IV (Col IV) is one of the major components of the basement membrane. Increased synthesis leads to glomerulosclerosis (3). Additionally, chronic inflammation is associated with abnormal ECM deposition. These alterations are involved in the occurrence and development of DN (4). Platelet-activating factor (PAF) has been reported to be a strong inflammatory factor and may damage renal tissue in a variety of ways (5). A high glucose (HG) and lysophosphatidylcholine (LPC) environment increases the expression of inflammatory cytokines, leading to the stimulation of MCs and endothelial cells to continuously synthesize PAF, ECM and protein kinase C-β1 (PKC-β1) (5). PKC is aberrantly activated in the diabetic kidney, which causes an increase in PKC-β1 activity and the deposition of ECM proteins, including Fn and Col IV (6).
In addition to their lipid lowering effects, statins may inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (7). Studies have reported that atorvastatin may significantly reduce the plasma levels of C-reactive, interleukin (IL)-1β, IL-6, tumor necrosis factor-α and other inflammatory markers in patients with Alzheimer's disease (8). Furthermore, statins inhibit HG- and LPC-induced secretion of the ECM (9). These notable effects of statins may be present due to their lipid-lowering and anti-inflammatory actions, in addition to their pleiotropic effects. As a result, statins have been used not only in cardiovascular disease, but for other conditions, including DN (10). However, more evidence in properly designed trials is required to determine whether the protective effect of atorvastatin on the kidney is associated with PAF and PKC-β1. In the present study, it was demonstrated that atorvastatin may reduce the secretion of Fn and Col IV in human (H)MCs in a HG and LPC environment, by reducing the increase in PAF secretion via inhibition of PKC-transforming growth factor-β1 (TGF-β1) signaling.
Materials and methods
Cell culture
Immortalized HMCs (donated by Professor Sun Zilin, Department of Endocrinology, Zhongda Hospital affiliated with Southeast University, Nangjing, China) (11), were obtained by double transfection with T-SV40 and H-ras proto-oncogene. These cells retain the basic morphology and biological characteristics of normal human glomerular MCs (12). The cells were maintained in a sterile incubator with 10% fetal calf serum (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA) and Dulbecco's modified Eagle's medium (DMEM; Thermo Fisher Scientific Inc.) in a humidified atmosphere with 5% CO2 at 37°C. When cells had reached 90% confluency, cells were seeded into 6-well plates (6×105 cells/well) and then incubated at 37°C and 5% CO2 for 12 h.
Cells were then divided into three groups: A, control [5.5 mmol/l D-glucose (Enzo Life Sciences, Inc., Farmingdale, NY, USA)] (11); B, HG+LPC group [30 mmol/l D-glucose+20 mg/l LPC (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany)]; C, atorvastatin [30 mmol/l D-glucose+20 mg/l LPC+10 µmol/l atorvastatin (Pfizer Inc., New York, NY, USA)]. Group C was pretreated with atorvastatin for 1 h prior to the addition of 30 mmol/l D-glucose and 20 mg/l LPC. Following ≥24 h, the supernatant of all three groups was collected and the experiments were repeated three times.
ELISA analysis
The expression levels of Fn, Col IV and PAF in the supernatant of each group was determined by ELISA. Human FN ELISA kit (NeoScientific, Cambridge, MA, USA; cat. no. HF0011), Human Col IV ELISA kit (NeoScientific; cat. no. HC0787), Human PAF ELISA kit (NeoScientific; cat. no. HP0596). The method was performed according to the manufacturer's protocol Each group was set up in three wells in order to repeat the experiment three times.
Detection of PAF receptor (PAF-R), GADPH, PKC-β1 and TGF-β1 expression in HMCs by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Total RNA was extracted using TRIzol reagent (Invitrogen; Thermo Fisher Scientific, Inc.), according to the manufacturer's protocol. The RT reaction was performed using the Revert Aid First Strand cDNA Synthesis reagent (Fermentas; Thermo Fisher Scientific, Inc.) at 42°C for 15 min and 95°C for 3 min, followed by 4°C for 5 min; according to the manufacturer's protocol. PAF-R primer sequences were as follows: Forward, 5′-TGCCCCTGCTACAGGCACCA-3′ and reverse, 5′-TGCTGTAAACAATCGGGAAGAG-3′. GAPDH primers sequences were as follows: Forward, 5′-ACACCCACTCCTCCACCTTT-3′ and reverse, 5′-TTACTCCTTGGAGGCCATGT-3.
PKC-β1 primer sequences were as follows: Forward, 5′-GGGGGCGACCTCATGTAT-3′ and reverse, 5′-GCAATTTCTGCAGCGTAAAA-3′. TGF-β1 primer sequences were as follows: Forward, 5′-ACTACTACGCCAAGGAGGTCAC-3′ and reverse, 5′-TGCTTGAACTTGTCATAGATTTCG-3′. Primers were designed using Premier Oligo 5 and Primer 6.22 software (Premier Biosoft International, Palo Alto, CA, USA). qPCR assays were performed using a QuantStudio 5 Real-Time PCR System (Thermo Fisher Scientific, Inc.) in a 20 µl PCR volume using iQ SyBr Green Supermix for 10 sec at 95°C, followed by 40 cycles of 56°C for 20 sec and 72°C for 10 sec. The quantification cycle (2−ΔΔCq) method was used to calculate the relative changes in expression levels (13). Each sample was prepared in triplicate, and the results are expressed as the mean of three independent experiments.
Western blotting
The cells were lysed using a HMC lysis buffer (Promega Corporation, Madison, WI, USA). Lysates were transferred into an Eppendorf tube and centrifuged at 12,000 × g for 15 min at 4°C. The supernatant was collected, and the concentration of protein was determined by ultraviolet spectroscopy (14). Protein (50 µg) were separated by 5% SDS-PAGE (Bio-Rad Laboratories Inc., Hercules, CA, USA) and transferred onto a nitrocellulose membrane (Bio-Rad Laboratories, Inc.). The membrane was incubated in TBS with 0.1% Tween-20 (TBST) and 5% fat-free milk for 1 h at 37°C. The proteins were detected with the addition of primary antibodies which were left to incubate overnight at 4°C (Sigma-Aldrich; Merck KGaA). The dilution ratios were as follows: TGF-β1 (Santa Cruz Biotechnology, Inc., Dallas, TX, USA; cat. no. SC-130348; 1:2,000); PKC-β1 (Santa Cruz Biotechnology, Inc.; cat. no. SC-8393; 1:400) and GAPDH (Santa Cruz Biotechnology, Inc.; cat. no. SC-32233; 1:3,000). Following washing with TBST, membranes were incubated with horseradish peroxidase-conjugated secondary antibodies (Santa Cruz Biotechnology, Inc.; cat. no. SC-516245; 1:5,000) for 1 h at 4°C, followed by additional washes with TBST. Protein bands were visualized by enhanced chemiluminescence (Pierce; Thermo Fisher Scientific, Inc.). The Scion Image 4.03 system (National Institutes of Health, Bethesda, MD, USA) was used to quantify band intensity, and results are expressed as the mean of three independent experiments.
Antibodies, immunoprecipitation and immunoblotting
Cells (2×104 cells/ml) were cultured on coverslips in 24-well plates and serum-starved for 24 h. The cells were subsequently fixed with 4% paraformaldehyde for 5 min at −20°C and blocked for 30 min in 0.2% Triton X-100 in PBS. The cells were incubated with aforementioned primary antibodies (1:50) overnight at 4°C, followed by fluorescein isothiocyanate-conjugated secondary anti-mouse IgG antibodies (Dako; Agilent Technologies, Inc., Santa Clara, CA, USA) for 1 h in the dark at room temperature. Following three washes in PBS, coverslips were placed on slides and visualized by confocal microscopy (magnification, ×400). Fluorescence intensity was analyzed using Image J software (version 1.48; National Institutes of Health).
Statistical analysis
All data are presented as the mean ± standard deviation. Data was analyzed using SPSS 18.0 software (SPSS, Inc., Chicago, IL, USA) for Windows. Multigroup comparisons of the means were performed using one-way analysis of variance test followed by the Newman-Keuls post hoc test. Differences between two groups were assessed by Student's t-test. α=0.05 and P<0.05 was considered to indicate a statistically significant difference.
Results
Atorvastatin inhibits the expression of Fn and Col IV in HMCs
Levels of Fn and Col IV in the supernatant of the HG+LPC group were significantly higher compared with the control group (P<0.05). In the presence of atorvastatin their levels were significantly decreased (Table I; Figs. 1 and 2).
Atorvastatin inhibits the expression of PAF and PAF-R mRNA in HMCs
Compared with the control group, the expression of PAF and PAF-R mRNA was significantly higher in the HG+LPC group (P<0.05). Atorvastatin inhibited the increase in PAF content in the supernatant of HMCs (P<0.05) (Table II; Fig. 3), in addition to the expression of the PAF-R mRNA gene in the HG+LPC environment (P<0.05; Table II; Fig. 4).
 | Table II.Effects of atorvastatin on the expression of PAF and PAF-R mRNA gene in human mesangial cells. |
Atorvastatin inhibits the expression of TGF-β1 in HMCs
TGF-β1 expression is upregulated in HMCs in the presence of PAF, HG and LPC. TGF-β1 mRNA (Table III; Fig. 5) and protein (Fig. 6) expression levels were increased in HMCs treated with HG+LPC relative to the control (P<0.05). Expression was significantly lower in cells treated with atorvastatin compared with those treated with HG+LPC only (P<0.05).
Atorvastatin inhibits the expression of PKC-β1 in HMCs
Detection of PKC-β1 mRNA expression in HMCs in each group by RT-qPCR revealed that mRNA levels were significantly higher in the HG+LPC group compared with the control (P<0.05). The expression was significantly higher in the HG+LPC group compared with cells treated with HG+LPC+atorvastatin (P<0.05). Thus, atorvastatin may inhibit the expression of PKC-β1 mRNA in HMCs (Table IV; Fig. 7).
Detection of PKC-β1 protein expression in HMCs in each group by western blotting
PKC-β1 protein (Fig. 8) expression levels were significantly increased in HMCs treated with HG+LPC relative to the control (P<0.05). Expression levels were significantly lower in cells treated with atorvastatin compared with those treated with HG+LPC only (P<0.05).
Effect of atorvastatin on the expression and localization of PKC-β1 in HMCs
In control cells, PKC-β1 immunofluorescence was diffusely distributed throughout the cytoplasm, with no membrane or nuclear localization. Treatment with HG and LPC increased PKC-β1 protein expression levels, and induced the translocation of the protein from the cytoplasm to the nucleus. These effects were reduced in cells treated with atorvastatin (Fig. 9).
Mean fluorescence intensity of PKC-β1 in HMCs under various treatment conditions
The mean fluorescence intensity of PKC-β1 in HMCs was significantly increased in the HG+LPC group compared with the control (P<0.05). The addition of atorvastatin to the HG+LPC environment significantly reduced the mean fluorescence intensity (P<0.05; Table V; Fig. 10).
| Table V.Mean fluorescence intensity of PKC-β1 in human mesangial cells under various treatment conditions. |
Discussion
Statins have the potential to be used to treat DN. This disease is thought to be triggered by abnormal ECM deposition and a decrease in the glomerular filtration rate. Morphometric studies on HMCs in a HG environment provide convincing evidence that Col IV and Fn are increased, which partially explains the occurrence of glomerular sclerosis and renal failure (15,16). Genetic and environmental factors contribute to renal failure. For example, patients with diabetes may have increased concentrations of PAF, a potent pro-inflammatory factor implicated in the pathogenesis of DN (17). Under certain stimuli, various cell types may secrete PAF, including platelets, endothelial cells and MCs (18). The primary source of PAF, however, is the kidney, in which 20–25% of PAF is secreted by MCs (19). MCs are the principal component of the glomerular filtration barrier and excessive expression of PAF may cause damage to this interface. A previous study reported that PAF is able to promote the secretion of the ECM (20). Excessive secretion of ECM deposition in MCs results in the development of glomerular sclerosis (20). The PAF-R is a G protein coupled receptor that is expressed on MCs. The binding of PAF triggers downstream signaling pathways resulting in the production of effector molecules, including arachidonic acid, prostacyclin and TGF-β1 which, in turn, regulate ECM secretion (5,21). The expression of PAF-R mRNA has been detected in all cells of the kidney, and its levels depend on the amount of PAF present. In a model of unilateral ureteral obstruction, PAF-R expression increased by 70-fold (22), revealing that an inflammatory environment may stimulate the kidney to secrete PAF, and the increase in PAF secretion, in turn, increases the expression of the PAF-R. In a mixed culture model of rat and human MCs, it was demonstrated that PAF was able to upregulate ECM secretion (23); a corresponding increase in Fn and Col IV was additionally observed in this model (24). To support this observation, it was confirmed in the present study that pretreatment of the HMCs with HG and LPC significantly increased Col IV and Fn via the induction of PAF.
Inflammatory factors promote the expression of TGF-β1 by activating the PKC-dependent pathway; this stimulates the synthesis of Fn (16). In line with this statement, a rise in PAF activity in the cells exposed to HG+LPC was observed in the present study, which was concomitant with an increase in Fn, Col IV and PKC-β1. PAF has detrimental effects in MCs, and this may be through the activation of the PKC-β1 signaling pathway, which leads to increased expression of ECM proteins (16). It has been previously reported that HG may activate the PKC-β1 pathway and promote the secretion of TGF-β1 in MCs. TGF-β1 may further stimulate the synthesis of collagen III and IV, Fn and other ECM components (15). Consistent with these findings, the present study demonstrated that an increase in PAF expression in cells exposed to HG+LPC was associated with increased levels of PKC-β1 and TGF-β1. This finding may indicate that PAF induces a molecular cascade that activates PKC-β1, leading to ECM accumulation and glomerular sclerosis (21).
Statins have been widely used as lipid-lowering drugs to exert a protective effect on endotheliocytes. Statins reduce cardiovascular morbidity and mortality in patients with end-stage renal disease (25). This effect of statins may be due to their lipid-lowering effects, in addition to their pleiotropic effects, including the ability to promote endothelial repair, and reduce inflammation and oxidative stress (26). Atorvastatin inhibits the HG-induced secretion of Col IV and Fn, mesangial matrix deposition and mesangial cell proliferation (27,28). Atorvastatin has been reported to have anti-fibrotic effects in chronic kidney disease (9). Essentially, atorvastatin has the ability to reduce glomerular mesangial ECM deposition, and thus delay the progression of glomerular sclerosis (29). A previous study demonstrated that statins inhibit the production of PAF, and this action may be through the inhibition of TGF-β1 and reactive oxygen species as well as the expression of other cytokines, in addition to mothers against decapentaplegic homolog protein expression in glomerular MCs, thus inhibiting Fn and Col IV secretion (9). A recent report observed that statins may suppress PAF production (30), and they may therefore effectively treat cardiovascular diseases, and conditions including diabetes (31) and DN (32). The present study revealed that atorvastatin reduced the PAF content in MCs in a HG and LPC environment. This may be associated with the upregulation of PAF-acetylhydrolase activity (33), leading to an increase in PAF degradation and thus reducing the renal protective effect of ECM secretion in the culture model. The present study additionally demonstrated that the expression of the PAF-R gene in the HMCs in the atorvastatin-pretreated group was significantly decreased compared with the HG and LPC group. This suggested that atorvastatin may inhibit the expression of the PAF-R gene in HMCs induced by HG and LPC. The expression of the PAF-R gene in MCs is associated with nuclear factor-κB (NF-κB) activity. HG and LPC may activate the PKC-NF-κB pathway in MCs, which subsequently increases the transcription of the PAF-R gene (34). However, the present study identified that when the PAF-R gene was significantly increased, PKC-β1 and TGF-β1 were increased. Therefore, it may be hypothesized that atorvastatin may inhibit the expression of the PAF-R gene in HG and LPC induced HMCs by inhibiting the activation of TGF-β1, and inhibiting the PKC pathway. However, the specific mechanism remains unclear and requires further investigation.
In the present study, the expression of PKC-β1 mRNA and protein in HMCs pretreated with atorvastatin was significantly lower compared with groups treated with HG and LPC alone. Immunofluorescence indicated that the expression of PKC-β1 in the cytoplasm and nucleus was additionally reduced, suggesting that atorvastatin may inhibit the activation of the PKC pathway under the conditions of HG and LPC. Simvastatin inhibits inflammatory and oxidative stress by inhibiting the activation of the PKC pathway, thus exerting a protective effect in patients with chronic kidney disease (35). Atorvastatin may inhibit the expression of TGF-β1, which may alleviate the local inflammatory reaction of the kidney (36). In the present study, suppression of PKC-β1 signaling by atorvastatin is partly responsible for the reduced levels of PAF and ECM. These results all suggest that atorvastatin may alter the activation of the PKC-β1/TGF-β1 pathway to reduce ECM secretion in HMCs stimulated by HG and LPC, although the specific mechanism remains unclear and further research is required.
In conclusion, the results of the present study suggested that atorvastatin may reduce the secretion of ECM proteins (Fn and Col IV) by inhibiting the secretion of PAF, the expression of PAF-R, and the activation of the PKC-β1/TGF-β1 signaling pathway in HMCs under HG and LPC conditions. Additionally, these findings revealed that atorvastatin may delay glomerular fibrosis by inhibiting the PKC-β1/TGF-β1 signaling pathway in HMCs. This mechanism may contribute to the efficiency of atorvastatin for the treatment of DN.
Acknowledgements
The authors gratefully acknowledge Professor Sun Zilin from the Zhongda Hospital Affiliated with Southeast University (Nangjing, China), for the donation of immortalized human mesangial cells. The authors would also like to thank the Science and Research Center, Guilin Medical University (Guilin, China) for their technical support.
Funding
The present study was supported by the National Natural Science Foundation of China. Grant: Research on the relationship between insulin resistance of podocytes in diabetic neuropathy (grant no. 81560148).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SXZ designed the study. YHX and XYH performed the experiments, and YHX was the major contributor in the writing of the manuscript. QH and FY analyzed the data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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