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BY 4.0 license Open Access Published by De Gruyter Open Access December 7, 2022

Plant-derived bisbenzylisoquinoline alkaloid tetrandrine prevents human podocyte injury by regulating the miR-150-5p/NPHS1 axis

  • Yue Sun , Chenyi Yuan , Jin Yu , Caifeng Zhu , Xia Wei and Jiazhen Yin EMAIL logo
From the journal Open Chemistry

Abstract

Podocytes have become a crucial target for kidney disease. Tetrandrine (TET), the main active component of a Chinese medicine formula Fangji Huangqi Tang, has shown a positive effect on various renal diseases. We aimed to investigate the effect and mechanism of TET on podocytes. The targeting relationship between microRNA (miR)-150-5p and nephrosis 1 (NPHS1) was determined by a dual-luciferase reporter gene assay. Cell proliferation, migration, and apoptosis were detected by cell counting kit-8, Transwell, and flow cytometry assays, respectively. The expression of miR-150-5p and NPHS1 was detected by RT-qPCR. The levels of Nephrin, Caspase-3, Bcl-2, Bax, E-cadherin, and α-smooth muscle actin were detected by Western blot. TET prompted cell viability and inhibited migration and apoptosis of puromycin aminonucleoside-induced human podocytes (HPC) in a dose-dependent manner. miR-150-5p directly targeted NPHS1 and was upregulated in damaged HPC. TET decreased the miR-150-5p expression and increased the level of NPHS1 and Nephrin. Overexpressed miR-150-5p inhibited the expression of NPHS1 and Nephrin, and reversed the protective effects of TET on injured HPC. TET protects the biological function of HPC by suppressing the miR-150-5p/NPHS1 axis. It reveals that TET may be a potential drug and miR150-5p is a potential therapeutic target for the treatment of podocyte injury.

1 Introduction

Podocytes are highly differentiated glomerular visceral epithelial cells with enormous cell bodies and extending foot processes, which are integral components of the renal glomerular filtration barrier [1]. Podocytes are susceptible to a variety of injuries and therefore, they undergo a series of alterations including hypertrophy, detachment, autophagy, and apoptosis [2]. Podocyte injury is the primary cause of glomerular disease [3]. Podocytes participated in the pathogenesis of kidney diseases, for instance, minimal change disease and diabetic nephropathy [4,5]. Therefore, protecting and restoring podocytes from harmful factors is a major challenge in kidney disease treatment.

Tetrandrine (TET) is a natural bisbenzylisoquinoline alkaloid extracted from the root of Stephania tetrandra [6]. As a key component in Fangji Huangqi Tang, which is a well-known traditional Chinese medicine formula for nephrotic syndrome [7,8], TET shows various biological activities, including anti-inflammation and anti-bacterial [9,10]. TET has been proven to alleviate proteinuria and ameliorate renal function [11]. TET promoted mitochondrial autophagy and blocked apoptosis in the kidney of nephritis rats [12]. In diabetic nephropathy, TET could restrain the diabetic process and renal damage [13]. Yu et al. found that TET suppressed damage by blocking RhoA/ROCK1 signaling in mice podocytes [14]. However, the effects of TET on human podocytes (HPC) are little known.

MicroRNAs (miRNAs), a group of small non-coding RNAs with lengths ranging from 18 to 25 nucleotides, perform post-transcriptional regulation functions through binding to target genes [3,15]. miRNAs are capable of modulating vital biological progressions, such as proliferation, migration, and apoptosis [16]. Several studies demonstrated that miRNAs play a crucial role in pathogenesis of diabetic nephropathy, including podocyte injury. For instance, inhibition of miR-155 alleviates podocyte inflammation [17]. miR-671-5p is critical in mediating WT1 depletion and podocyte injury [18]. miR-150-5p, an immune-related miRNA, was discovered to inhibit cell proliferation and migration [1921]. Recently, silencing of miR-150-5p was reported to ameliorate diabetic nephropathy [22]. Previous research also has shown that TET functions via miRNAs. TET improves myocardial ischemia-reperfusion injury by miR-202-5p and attenuates intestinal epithelial barrier defects through AhR-miR-429 pathway [23,24]. However, studies about the effects of TET on podocytes biological function through miR-150-5p are limited.

Therefore, the goal of current study was to examine the therapeutic effect and the underlying mechanism of TET on podocyte injury in order to provide fresh light on how to prevent nephropathy caused by podocyte damage.

2 Methods

2.1 Cell culture and treatment

HPC were acquired from China Center for Type Culture Collection (Wuhan, China). All cells were cultured in Roswell Park Memorial Institute 1640 medium with 10% fetal bovine serum (Hyclone, UT, USA) at 33°C in 5% CO2. After reaching 80% confluence, cells were transferred to a 96-well plate to initiate cell differentiation into mature podocytes for at least 14 days in a 37°C incubator. Subsequently, 100 μg/mL puromycin aminonucleoside (PAN; Abcam, Cambridge, UK) was added to the medium for 24 h. Then, all cells were treated with 1.5, 6.25, or 12.5 µg/mL TET (Solarbio, Beijing, China).

2.2 Cell transfection

Cells were grown to a confluent of 70–80% and then 2 ×  105 of which were placed into 24-well plates. After culturing for 24 h, part of the cells was co-transfected with luciferase plasmids of wild-type (WT)-, mutant-type (MUT)-nephrosis 1 (NPHS1), and miR-150-5p mimics. Other cells treated with PAN and TET were transfected with miR-150-5p or negative control (NC) mimics (Thermo Fisher Scientific, MA, USA). Transfection was performed using Lipofectamine 3000 (Invitrogen, CA, USA) in accordance with manufacturer’s instructions to achieve 50 nM final concentration. After the reagent was added for 48 h, transfected cells were collected.

2.3 Dual-luciferase reporter gene assay

The pmirGLO dual-luciferase vector (Promega, WI, USA) containing NPHS1 3′-untranslated regions (3′-UTR) was co-transfected with miRNA mimic into HPC. Then the constructed NPHS1-WT/MUT vectors were co-transfected with miR-150-5p mimics or mimics-NC. Activities of both firefly and Renilla luciferases were assessed using a dual-luciferase reporter gene assay kit (Thermo Fisher Scientific). Transfected cells were lysed with 100 µL 1× passive lysis buffer. The supernatant of the lysate was obtained after being centrifuged at 10,000g for 5 min. Then, 10 μL supernatant was placed into an opaque 96-well plate and added with 100 μL LARII and Stop & Glo Reagent. Luciferase activity was assessed with a SpectralMax M4 multifunctional microplate reader (Molecular Devices, CA, USA).

2.4 Cell counting kit-8 (CCK-8) assay

Cell viability was evaluated with a CCK-8 kit (Beyotime, Shanghai, China). Cells were trypsinized and inoculated at 100 µL/well in a 96-well plate. CCK-8 (10 μL) solution was added at 24 h and incubated for 2 h at 37°C. Absorbance at 450 nm was examined on a microplate reader (Bio-Rad, CA, USA).

2.5 Flow cytometry

Cells were digested with 0.25% trypsin without ethylenediaminetetraacetic acid (Beyotime) and were suspended twice with pre-cold phosphate buffered saline. Cells were resuspended to 1  ×  106 cells/mL concentration after centrifuging at 1,500 rpm for 5 min. Following incubation with 5 µL Annexin V-FITC (Beyotime) for 15 min in dark, cells were incubated with 10 µL PI for 10 min in dark. CELL Quest software (Beckman, CA, USA) was used to assess apoptosis.

2.6 Transwell assay

The 24-well chambers (Corning, NYC, USA) were used to perform Transwell migration assay. The lower chamber was added with 600 µL medium, and the upper chamber was added with HPC (1 ×  105 cells/mL) in 200 μL serum-free medium. Cells were cultured for 24 h before being fixed with 4% methanol anhydrous for 30 min and dyed with crystal violet (Beyotime) for 20 min. The cells’ number was calculated. Finally, cells were captured via light microscope (Olympus, Tokyo, Japan) with randomly selected nine non-overlapping fields.

2.7 Real time-quantitative polymerase chain reaction (RT-qPCR)

Total RNAs were extracted by Trizol reagent (Invitrogen, CA, USA). cDNA was obtained by the PrimeScriptTM RT Reagent kit (Invitrogen). PCR was carried out with SYBR Green reagent (Lifeint, Xiamen, China) on the Mx3000P fast RT-PCR System (Agilent Stratagene, Shanghai, China). RT-qPCR detection was conducted at 95°C for 3 min, 40 cycles at 95°C for 12 s and 62°C for 40 s. GAPDH was taken as endogenous control of NPHS1, and U6 was adopted as endogenous control of miR-150-5p. Gene expressions were assessed using the 2−ΔΔCt method. Primers in this study are presented in Table S1.

2.8 Western blot

Proteins were extracted by radioimmunoprecipitation lysis buffer (Beyotime). BCA kit (Thermo Fisher) was utilized to detect the protein concentration. The proteins (25 μg) were divided using 10% (w/v) SDS-PAGE and then placed onto the polyvinylidene difluoride membrane, which were blocked with milk for 1 h. Primary antibodies Nephrin (1:5,000, ab136894; Abcam, Cambridge, UK), Caspase-3 (1:5,000, ab32351; Abcam), Bcl-2 (1:1,000, ab32124; Abcam), Bax (1:1,000, ab32503; Abcam), E-cadherin (1:10,000, ab76319; Abcam), α-smooth muscle actin (α-SMA; 1:1,000, 19245; Cell Signaling Technology, MA, USA), and GAPDH (1:2,500, ab9485; Abcam) were added and incubated overnight at 4°C. Membranes were washed thrice with 1×  TBST buffer and further treated with secondary antibody goat anti-rabbit IgG H&L (1:2,000, ab205718; Abcam) for 1 h. Protein bands were visualized using an enhanced chemiluminescence (Thermo Fisher Scientific) and photographed on a gel imager system (Bio-Rad).

2.9 Statistical analysis

Each experiment was repeated thrice. Data are presented as mean ± standard deviation. Differences among groups were determined with the analysis of variance, followed by Tukey’s test. Statistical analysis was evaluated using GraphPad Prism 8.0 (GraphPad, CA, USA). P < 0.05 was regarded as statistically significant difference.

  1. Ethical approval: The conducted research is not related to either human or animal use.

3 Results

3.1 TET stimulated proliferation, and inhibited migration and apoptosis of injured HPC

To investigate the effect of TET on HPC, PAN was utilized to induce HPC injury, and podocytes were treated with different concentrations of TET (1.5, 6.25, or 12.5 μg/mL). CCK-8 revealed that cell viability declined in injured cells compared to control cells. However, TET increased the cell viability (P < 0.05; Figure 1a). In comparison with the control cells, flow cytometry assay revealed that apoptosis increased in HPC following injury while TET suppressed apoptosis (P < 0.05; Figure 1b). Transwell assay demonstrated that TET inhibited migration of injured HPC (P < 0.01; Figure 1c). Bax and Caspase-3 are apoptosis-related proteins, and Bcl-2 is an inhibitor of apoptosis protein. Western blot revealed that TET decreased the level of Bax and Caspase-3 while increasing the Bcl-2 expression in injured HPC (P < 0.05). E-cadherin is an epithelial–mesenchymal transition (EMT)-related protein and α-SMA is a key profibrotic protein. Western blot showed that TET upregulated the E-cadherin level, but downregulated the α-SMA level (P < 0.05). Nephrin, encoded protein of NPHS1, is a podocyte-related protein. Our data demonstrated that TET prompted the Nephrin level in injured HPC (P < 0.05; Figure 1d). Noteworthy, TET exerted its protective effects on HPC in a concentration-dependent manner. Thus, cells treated with 12.5 μg/mL TET were selected for further experiments.

Figure 1 
                  TET positively stimulated proliferation, and inhibited migration and apoptosis of injured HPC. (a–c) CCK-8, flow cytometry, and Transwell assays detected the cell proliferation, apoptosis, and migration, respectively; scale bar = 50 μm. (d) Western blot detected the levels of Bax, Bcl-2, Caspase-3, E-cadherin, α-SMA, and Nephrin. PAN-induced HPC were treated with TET (1.5, 6.25, or 12.5 μg/mL). **
                     P < 0.01 vs control group; #
                     P < 0.05, ##
                     P < 0.01 vs PAN group; &
                     P < 0.05, &&
                     P < 0.01 vs PAN + 1.5 μg/mL TET group; @
                     P < 0.05, @@
                     P < 0.01 vs PAN + 6.25 μg/mL TET group.
Figure 1

TET positively stimulated proliferation, and inhibited migration and apoptosis of injured HPC. (a–c) CCK-8, flow cytometry, and Transwell assays detected the cell proliferation, apoptosis, and migration, respectively; scale bar = 50 μm. (d) Western blot detected the levels of Bax, Bcl-2, Caspase-3, E-cadherin, α-SMA, and Nephrin. PAN-induced HPC were treated with TET (1.5, 6.25, or 12.5 μg/mL). ** P < 0.01 vs control group; # P < 0.05, ## P < 0.01 vs PAN group; & P < 0.05, && P < 0.01 vs PAN + 1.5 μg/mL TET group; @ P < 0.05, @@ P < 0.01 vs PAN + 6.25 μg/mL TET group.

3.2 TET regulated the miR-150-5p/NPHS1 in the injured HPC

MiRNAs function as negative gene expression regulators by targeting mRNA complementary 3′-UTR sequence. The direct interaction of miR-150-5p and NPHS1 was verified using WT or MUT NPHS1 mRNA including a luciferase reporter plasmid. Our data revealed that HPC co-transfected with miR-150-5p mimics had lower fluorescence intensities in the WT-NPHS1 group, and there was no significant difference in MUT-NPHS1 group. Loss of binding sites eliminated the miR150-5p inhibitory effect on luciferase activity (P < 0.05; Figure 2a). These confirmed that NPHS1 was a direct downstream target of miR150-5p. Moreover, RT-qPCR showed that miR-150-5p level was overexpressed, while NPHS1 level was reduced in damaged podocytes, and TET intervention reversed these changes (P < 0.05, Figure 2b)

Figure 2 
                  MicroRNA-150-5p (miR-150-5p) directly targeted NPHS1. (a) Dual-luciferase reporter gene assay detected the target relationship between the miR-150-5p and NPHS1 (*
                     P < 0.05). (b) RT-qPCR detected the expression of miR-150-5p and NPHS1. PAN-induced HPC were treated with TET (1.5, 6.25, or 12.5 μg/mL). **
                     P < 0.01 vs control group; #
                     P < 0.05, ##
                     P < 0.01 vs PAN group; &&
                     P < 0.01 vs PAN + 1.5 μg/mL TET group; @
                     P < 0.05, @@
                     P < 0.01 vs PAN + 6.25 μg/mL TET group.
Figure 2

MicroRNA-150-5p (miR-150-5p) directly targeted NPHS1. (a) Dual-luciferase reporter gene assay detected the target relationship between the miR-150-5p and NPHS1 (* P < 0.05). (b) RT-qPCR detected the expression of miR-150-5p and NPHS1. PAN-induced HPC were treated with TET (1.5, 6.25, or 12.5 μg/mL). ** P < 0.01 vs control group; # P < 0.05, ## P < 0.01 vs PAN group; && P < 0.01 vs PAN + 1.5 μg/mL TET group; @ P < 0.05, @@ P < 0.01 vs PAN + 6.25 μg/mL TET group.

3.3 TET prevented podocyte injury through the miR-150-5p/NPHS1 axis

In previous experiments, TET was confirmed to suppress the miR-150-5p expression. To explore the underlying mechanism of TET on HPC biological function, miR-150-5p mimics were transfected into PAN-induced HPC that was treated with TET. Our data showed that miR-150-5p level was successfully increased after being transfected with miR-150-5p mimic, and miR-150-5p overexpression inhibited NPHS1 level (P < 0.05, Figure 3a). Furthermore, miR-150-5p upregulation reversed the protective effects of TET on podocyte injury. Cell viability was declined while the migration and apoptosis were enhanced after transfecting with miR-150-5p mimic (P < 0.05, Figure 3b–d). TET enhanced the proliferation, and retarded the migration and apoptosis of PAN-induced HPC, while miR-150-5p overexpression reversed these effects (P < 0.05; Figure 3a–e). In comparison with PAN + TET + NC mimic cells, miR-150-5p overexpression reduced the level of Bcl-2, E-cadherin, and Nephrin, while improving level of Bax, Caspase-3, and α-SMA (P < 0.05; Figure 3e).

Figure 3 
                  TET prevented podocyte injury through the miR-150-5p/NPHS1 axis. (a) RT-qPCR detected the expression of miR-150-5p and NPHS1. (b–d) CCK-8, flow cytometry, and Transwell assays detected the cell proliferation, apoptosis, and migration, respectively; scale bar = 50 μm. (e) Western blot detected the level of Bax, Bcl-2, Caspase-3, E-cadherin, α-SMA, and Nephrin. PAN-induced HPC were treated with 12.5 μg/mL TET and transfected with miR-150-5p mimics or NC mimics. **P < 0.01 vs control group. ##
                     P < 0.01 vs PAN group; @
                     P < 0.05, @@
                     P < 0.01 vs PAN + TET + NC mimic group.
Figure 3

TET prevented podocyte injury through the miR-150-5p/NPHS1 axis. (a) RT-qPCR detected the expression of miR-150-5p and NPHS1. (b–d) CCK-8, flow cytometry, and Transwell assays detected the cell proliferation, apoptosis, and migration, respectively; scale bar = 50 μm. (e) Western blot detected the level of Bax, Bcl-2, Caspase-3, E-cadherin, α-SMA, and Nephrin. PAN-induced HPC were treated with 12.5 μg/mL TET and transfected with miR-150-5p mimics or NC mimics. **P < 0.01 vs control group. ## P < 0.01 vs PAN group; @ P < 0.05, @@ P < 0.01 vs PAN + TET + NC mimic group.

4 Discussion

Podocyte is the most differentiated type in the glomerulus, which is essential for glomerular filtration barrier, and podocyte injury is the common pathological process in many glomerular diseases [5]. TET is reported to have potent bioactivities like antitumor, antimicrobial, anti-inflammatory, antioxidant, and calcium channel blocking effects [25]. Increasing studies show that miRNAs participate in the pathogenesis of nephropathy [26]. Present study demonstrated that TET improved cell viability and inhibited migration and apoptosis in PAN-induced podocytes. Besides, miR-150-5p directly targeted NPHS1, and TET downregulated the miR-150-5p level in injured podocytes. Further study revealed that TET protected the HPC biological function by miR-150-5p/NPHS1 axis.

TET is a naturally occurring alkaloid and has been well researched because of its numerous pharmacological properties, such as anti-inflammatory, anti-cancer, induction of autophagy, and so on [27,28]. TET has been reported to alleviate kidney disease [14]. TET can protect against membranous glomerulopathy [29]. Chen et al. found that TET inhibited migration and invasion of human renal cell carcinoma [30]. TET plays an important role in protecting against podocyte damage. It was reported that TET minimized proteinuria, enhanced renal function, and alleviated renal pathological damage in mice by blocking Ca2+-dependent calpain-1 signaling [31,32]. In order to investigate the impact of TET on HPC biological function, a PAN-induced podocyte injury model was established in vitro. Our findings demonstrated that podocyte viability declined after injury but advanced through TET intervention. Podocyte injury can lead to podocyte fusion and cytoskeleton rearrangement, which causes podocytes to apoptosis and acquire the ability to migrate [33]. Our results also found that expression of pro-apoptotic proteins (caspase-3 and Bax) were increased, while anti-apoptotic protein (Bcl-2) expression was decreased in damaged HPC. Besides, a large number of apoptotic and migratory podocytes were found in injured HPC. However, TET treatment reduced cell apoptosis and migration of podocyte injury. EMT is generally considered the central pathogenesis of podocyte injury [33,34]. It has been reported that inhibiting α-SMA expression and inducing E-cadherin expression ultimately prevent podocytes EMT [35]. In this study, TET treatment upregulated E-cadherin level and downregulated α-SMA expression. This result indicated that TET can ameliorate podocyte injury by preventing its EMT. Noticeably, high concentration of TET exhibited more significant protective effects on podocyte injury in our study. Altogether, TET protects the biological function of PAN-induced HPC in a dose-dependent manner.

MiRNA is an increasingly significant medium in the TET pharmacological activity [36]. It is hypothesized that miR-150-5p overexpression could serve as a diagnostic indicator for kidney diseases [3739]. NPHS1, encoding nephrotic protein (Nephrin), is related to the nephrotic syndromes [40]. Our finding demonstrated that miR-150-5p targeted NPHS1. A previous study has elucidated that high miR-150-5p level was detected in the serum of diabetic nephropathy patients [41]. Upregulated miR-150-5p level was found in our study, and the levels of NPHS1 and Nephrin were downregulated. These results showed a negative correlation between miR-150-5p and NPHS1. Additionally, TET reversed the expression of miR-150-5p and NPHS1. Therefore, we speculated that TET exerted pharmacological effects on HPC via miR-150-5p/NPHS1.

To identify the underlying mechanism of TET on podocyte injury, podocytes treated with TET were transfected with miR-150-5p mimics. Overexpressed miR-150-5p contributed to renal fibrosis following unilateral ischemia-reperfusion injury [42]. Silencing of miR-150-5p ameliorated diabetic nephropathy [22]. Our results revealed that overexpressed miR-150-5p reversed the protective effects of TET on damaged podocytes. Furthermore, miR-150-5p overexpression retarded the expression of NPHS1 and Nephrin in HPC treated with TET. These data verified that TET alleviated podocyte damage by inhibiting the miR-150-5p/NPHS1 axis.

5 Conclusion

In conclusion, our study confirmed that TET protects podocyte biological function via miR-150-5p/NPHS1 axis. This study provides novel insight into TET in the podocyte injury treatment. Nevertheless, there is lack of experiments in vivo and clinical studies on the role of TET on podocyte injury. Therefore, further investigations are imperative to resolve these issues.

Abbreviations

CCK

8-cell counting kit-8

EMT

epithelial–mesenchymal transition

HPC

human podocytes

MUT

mutant

NC

negative control

PI

propidium iodide

TET

tetrandrine


# These authors contributed equally to this work.


  1. Funding information: This work was supported by the Medical Health Science and Technology Project of Zhejiang Province (Protective effect of tetrandrine on podocyte injury in primary nephropathy through miR-150-5p/NPHS1 pathway) (Grant Number 2022KY268).

  2. Author contributions: Yue Sun: conceptualization, data curation, investigation, methodology, visualization, writing – original draft. Chenyi Yuan: data curation, formal analysis, methodology, software, writing – original draft. Jin Yu: data curation, formal analysis, software, validation. Caifeng Zhu: data curation, software, validation. Xia Wei: formal analysis, methodology, software, validation. Jiazhen Yin: conceptualization, funding acquisition, project administration, resources and supervision, writing – review and editing. All authors reviewed the results and approved the final version of the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Ethical approval: The conducted research is not related to either human or animal use.

  5. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2022-09-27
Revised: 2022-11-03
Accepted: 2022-11-20
Published Online: 2022-12-07

© 2022 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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