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Bioinformatics Analysis and Experimental Validation of Epigallocatechin-3-gallate Against Iopromide-induced Injury in HEK-293 Cells via Anti-oxidative and Anti-inflammation Pathways

YUH-FENG TSAI, CHIA-WEN TSAI, JAI-SING YANG, YU-NING JUAN, HOU-YU SHIH, DA-TIAN BAU and WEN-SHIN CHANG
In Vivo November 2024, 38 (6) 2617-2628; DOI: https://doi.org/10.21873/invivo.13738

Abstract

Background/Aim: The administration of contrast agents can adversely affect kidney function. Nevertheless, the nephrotoxicity of iopromide in human renal cells, potential therapeutic agents, and the underlying molecular mechanisms have not been thoroughly investigated. Materials and Methods: The proliferation of HEK-293 kidney cells was assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide (MTT) assay. Apoptotic cell death was examined using the TUNEL assay and caspase-3 activity measurements. The impacts and potential pathways of epigallocatechin-3-gallate (EGCG) on iopromide-induced renal damage were analyzed through whole transcriptome sequencing. The redox state was assessed by measuring reactive oxygen species (ROS) production and 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. Results: Iopromide-induced inhibition of cell proliferation and apoptosis in HEK-293 cells was counteracted by EGCG co-treatment. Pathway analysis revealed that molecules related to antioxidant and anti-inflammatory responses, such as ERK1/2, STAT1, and NF-Embedded ImageB, were pivotal in the action of EGCG. Conclusion: Iopromide-induced ROS production, decreased DPPH scavenging ability, DNA strand breaks, elevated caspase-3 activity, and reduced cell proliferation were all reversed by EGCG co-treatment in HEK-293 cells. The mechanisms likely involve the attenuation of oxidative stress, inflammatory responses, and apoptosis, with regulation through the ERK1/2, STAT1, and NF-Embedded ImageB pathways. Further research is necessary to confirm the protective effects of EGCG on renal function, particularly against damage induced by contrast agents like iopromide.

Key Words:

Iopromide is a widely used nonionic hypotonic contrast agent, particularly in percutaneous coronary interventions (1, 2). Clinically, there is a growing incidence of contrast-induced nephropathy among patients receiving contrast media (3, 4), sparking interest in predictive and preventive strategies (5-7). However, detailed studies specifically focusing on the nephrotoxicity of iopromide are scarce (2, 8). As early as 2013, Ludwig and colleagues identified that iopromide could induce DNA fragmentation in human kidney tubular epithelial HK-2 cells in a time- and concentration-dependent manner, though the severity was less compared to iodixanol, another contrast agent (9). In 2021, Dong and colleagues demonstrated that iopromide inhibited cell proliferation and induced apoptosis by increasing endoplasmic reticulum stress in the same cell line (10). In 2022, Pei and colleagues confirmed that iopromide inhibited cell proliferation and induced apoptosis in HK-2 cells and showed that salvianolic acid B could mitigate iopromide-induced injury (11). Renal safety remains a critical concern when using contrast agents. Current guidelines set risk thresholds for computed tomography (CT) imaging, particularly for patients with severe renal impairment (12, 13). However, the detailed mechanisms of iopromide-induced nephropathy need further exploration, especially considering the diversity of kidney cell types, to advance preventive and therapeutic strategies.

The health advantages of tea have been appreciated for centuries and are now widely validated by scientific research (14). Tea has been shown to offer a range of health benefits, including cancer prevention (15), cardiovascular protection (16), anti-inflammatory properties (17), and immunomodulatory effects (18). These health-promoting effects are largely attributed to polyphenols, such as catechins, caffeine, and theanine, with epigallocatechin-3-gallate (EGCG) being the most potent among the catechins (19, 20). EGCG is found not only in tea but also in fruits, particularly berries, and nuts (21, 22). A growing body of research is exploring the signaling pathways influenced by EGCG and its ability to modify the signaling initiated by cytotoxic agents (23-26). Notably, EGCG has been shown to mitigate acute kidney injury (27). Recently, the therapeutic potential of EGCG has been evaluated in clinical trials for various human diseases, including cervical cancer (28), ovarian cancer (29), endometrial cancer (29), Alzheimer’s disease (30), diabetes (31), and non-alcoholic fatty liver disease (32).

In our prior publication, we elucidated the intracellular pathways involved in iopromide-induced nephrotoxicity in HEK-293 cells, a widely utilized human kidney cell line (33). At the present study, we aimed to investigate the protective effects of EGCG on iopromide-induced nephrotoxicity through both bioinformatics analyses and experimental methods. Although numerous studies have explored contrast-induced nephropathy in recent years, the specific mechanisms by which iopromide causes renal injury remain underreported, and methods to counteract its adverse effects are even less discussed. Consequently, this study focuses on systematically evaluating the protective mechanisms of EGCG in HEK-293 cells subjected to iopromide-induced damage, providing a foundation for the prevention and treatment of iopromide-associated nephrotoxicity.

Materials and Methods

HEK-293 cell line and culture conditions. The HEK-293 human embryonic kidney cell line was obtained from the Bioresource Collection and Research Center (Hsinchu, Taiwan, ROC). Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum, 100 U/ml penicillin, 0.1 mg/ml streptomycin, and 2 mM L-glutamine. The cultures were maintained in an incubator set to 37°C with 5% CO2 and 95% humidity.

Reagents and chemicals. Iopromide (Ultravist®) was supplied by Dr. Yuh-Feng Tsai from the Department of Diagnostic Radiology at Shin-Kong Wu Ho-Su Memorial Hospital in Taiwan. Other reagents, including phosphate-buffered saline (PBS), dimethyl sulfoxide (DMSO), and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), were obtained from Sigma Chemical (Sigma Chemical Co., St. Louis, MO, USA).

Cell viability measurements. HEK-293 cells (0.8×104 cells/well) were seeded in 96-well plates and cultured for 24 h before being exposed to 50 mgI/ml iopromide for 48 h with or without various dosages of EGCG. Cell morphology was evaluated using a light microscope at 200× magnification (Leica Microsystems GmbH, Wetzlar, Germany) to identify signs of apoptosis. Cell viability was assessed with the MTT assay, as described in our previous publication (34). Briefly, cells were incubated with MTT for 4 h, and absorbance was measured at 570 nm using a SpectraMax iD3 multimode microplate reader (Molecular Devices Ltd., San Jose, CA, USA). Cell viability was expressed as a percentage relative to the untreated control group, which was set to 100%.

Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Apoptosis in HEK-293 cells was analyzed using microscopy, as previously described (35, 36). Nuclei were visualized using DAPI staining. Images were captured at 200× magnification using a fluorescence microscope (Eclipse Ti-U, Nikon Corporation, Tokyo, Japan) with excitation wavelengths of 405 nm for DAPI and 488 nm for TUNEL. The number of TUNEL-positive nuclei was quantified in 10 fields within the renal medulla per section from three different sections, with the examiner blinded to the experimental conditions. Data were presented as the average number of TUNEL-positive nuclei per 200× magnification field.

Caspase-3 activity assays. To assess changes in caspase enzymatic activity, the FAM FLICA Caspases-3 Assay Kit (MyBioSource, San Diego, CA, USA) was used, as described in our previous work (37). Briefly, HEK-293 cells were plated in 6-well plates at a density of 1×106 cells per well and incubated for 24 h. Following this, the cells were treated with iopromide at 50 mgI/ml, with or without EGCG, for an additional 48 h. The samples were then processed and analyzed using the NucleoCounter® NC-3000™ advanced image cytometer (ChemoMetec A/S, Bohemia, NY, USA).

Reactive oxygen species (ROS) production. HEK-293 cells (1×106 cells/total) were plated in 6-well plates and exposed to 50 mgI/ml of iopromide, with or without EGCG (100 or 200 μM), for 24 h. Following treatment, cells were stained with CM-H2DCFDA, a general oxidative stress indicator, at a concentration of 50 μM for 30 min at 37°C (Abcam, Cambridge, UK). The fluorescence intensity of the cells was subsequently measured using the NucleoCounter® NC-3000™ advanced image cytometer (ChemoMetec A/S) (33, 35).

2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The DPPH radical scavenging activity was assessed following the methodology outlined in our prior publication (38). A 0.10 mmol/l DPPH solution (2.0 ml) in anhydrous ethanol was mixed with 2.0 ml of the sample solutions in separate test tubes and incubated in the dark for 30 min. The absorbance of the samples was then measured at a wavelength of OD517 nm after incubation in the dark for 1 h. The percentage of DPPH scavenging activity (%) was calculated using the following formula: DPPH scavenging activity %=(A0-A1/A0)×100%. In the formula, A0 stands for absorbance of the control, and A1 stands for absorbance of the EGCG treatment.

Whole transcriptome sequencing. Total RNA was extracted using Trizol® (Invitrogen, Carlsbad, CA, USA). RNA concentration was determined with a ND-1000 spectrophotometer (Nanodrop Technology, Wilmington, DE, USA) at OD260 nm (39, 40). To remove DNA contamination, RNA samples were treated with DNase I for 30 min at 37°C, followed by 25 mM EDTA treatment for 5 min to inactivate the enzyme. This procedure was conducted using the MagNA Pure Compact automated system (Roche Applied Science, Indianapolis, IA, USA). All RNA sample preparation procedures of library preparation and sequencing were carried out according to the Illumina’s official protocol (Illumina, San Diego, CA, USA). SureSelect XT HS2 mRNA Library Preparation kit (Agilent, Santa Clara, CA, USA) was used for library construction followed by AMPure XP bead size selection (Beckman Coulter, Brea, CA, USA). Whole transcriptome sequencing was determined using the NovaSeq 6000 system of Illumina’s sequencing-by-synthesis (SBS) technology (Illumina). Sequencing data (FASTQ reads) were generated using Welgene Biotech’s pipeline based on Illumina’s basecalling program bcl2fastq (v2.20). The bcl2fastq conversion software v2.20 was used to convert BCL files from all Illumina sequencing platforms into FASTQ reads. Adaptor clipping and sequence quality trimming was performed using Trimmomatic (v0.36) with a sliding-window approach. HISAT2 (v2.0.1) was used for mapping next-generation sequencing reads to the human reference genome (GRCh38.p14). Differential expression analysis was performed using StringTie (StringTie v2.1.4) and DEseq (DEseq v1.39.0) with genome bias detection/correction. Genes with p-value <0.05 and log2 fold change <−1.0 or >1.0 were considered significantly differentially expressed. Every stage was performed under quality control and strict monitoring.

Bioinformatics network analysis. Volcano plots were produced by EnhancedVolcano. Bioinformatics network and pathway analysis were performed by Ingenuity Pathway Analysis (IPA) software (Qiagen Sciences, Inc., Germantown, MD, USA) Comparing biological themes among gene clusters was performed by the ClusterProfiler package (38, 41).

Statistical methodology. The statistical analysis was performed using SPSS 16.0 software (SPSS, Inc., IBM, Armonk, NY, USA). All data were presented as mean±standard deviation, compared by one-way ANOVA with Dunnett’s post hoc test or unpaired Student’s t-test. Each experiment was conducted at least thrice, and p-values less than 0.05 were considered to be statistically significant.

Results

EGCG did not affect the cell viability of HEK-293 cells. HEK-293 cells were exposed to 50 mgI/ml iopromide and varying concentrations of EGCG (0 to 200 μM) for 48 h. Cell viability was evaluated using the MTT assay. Firstly, EGCG did not adversely affect HEK-293 cell viability within 50-200 μM treatment for 48 h (Figure 1). The co-treatment experiments showed that EGCG mitigated the reduction in HEK-293 cell viability induced by iopromide in a dose-dependent manner at 0 to 200 μM EGCG (Figure 2). Observations of cell morphology after 48 h of treatment with 50 mgI/ml iopromide revealed cell shrinkage and rounding (Figure 2). These findings suggested that iopromide may induce apoptosis in HEK-293 cells, an effect that can be counteracted by EGCG.

Figure 1.
Figure 1.

Effect of cell viability on EGCG (50, 100 and 200 μM)-treated HEK293 cells. HEK-293 cells were treated with EGCG (50, 100 and 200 μM) for 24 h and cell viability was assessed using the MTT assay. The experiments were repeated thrice, and the data are presented as mean±standard deviation.

Figure 2.
Figure 2.

EGCG protected HEK-293 cells against the iopromide (50 mgI/ml)-induced cell viability decrease. (A) HEK-293 cells were treated with iopromide (50 mgI/ml) and/or EGCG (100 and 200 μM), and cell viability was measured with the MTT assay. Results were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test; ***p<0.001 and ###p<0.001. The experiments were repeated thrice, and the data are presented as mean±standard deviation. (B) Changes in the morphology of EGCG (100 and 200 μM)-treated HEK-293 cells.

EGCG could reverse iopromide-induced DNA strand breaks and caspase-3 activity in HEK-293 cells. Iopromide has been documented to cause nephrotoxicity in various renal cell types (10, 11). Our prior research established that high-dose treatments of iopromide (50-200 mgI/ml), for 24 or 48 h, lead to significant DNA strand breaks and increased caspase-3 activity in HEK-293 cells in both dose- and time-dependent manners (33). We now aimed to investigate whether EGCG can mitigate iopromide-induced DNA strand breaks and caspase-3 activity in HEK-293 cells. To explore this, HEK-293 cells were treated with 50 mgI/ml iopromide and concurrently treated with 100 or 200 μM EGCG to assess its effects on iopromide alone. The findings indicated that iopromide not only induced DNA strand breaks (Figure 3A) but also activated the apoptotic protein caspase-3 (Figure 3B). Caspase-3 is known to interact closely with caspases-8 and -9, which are integral to the apoptotic process.

Figure 3.
Figure 3.

EGCG protected HEK-293 cells against iopromide-induced apoptotic cell death. HEK-293 cells were treated with iopromide (50 mgI/ml) and/or EGCG (100 and 200 μM). (A) Apoptotic cells (TUNEL positive cells) were measured by the TUNEL assay. (B) Caspase-3 enzyme activity was measured. Results were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test; ***p<0.001 and ###p<0.001.

Bioinformatics and systematical analysis of EGCG against iopromide-induced renal nephrotoxicity. We then investigated the signaling mechanisms by which EGCG mitigates iopromide-induced nephrotoxicity. To this end, we performed whole-transcriptome sequencing to analyze differential RNA expression levels among 24,293 candidates in HEK-293 cells treated with iopromide alone versus those treated with iopromide and EGCG. The volcano plot presented in Figure 4 illustrates that 328 genes were significantly up-regulated, while 344 genes were down-regulated in response to treatment (Figure 4). Subsequently, we explored the pathways associated with these differentially expressed genes to assess the effects of EGCG on iopromide-treated HEK-293 cells. Ingenuity Pathway Analysis (IPA) identified 25 relevant metabolic pathways (Figure 5). The most prominent pathway was integrin cell surface interactions, followed by VDR/RXR activation, E1F2AK1 response to heme deficiency, and the wound healing signaling pathway. Further analysis revealed that key pathways and molecules involved in EGCG’s protective effect against iopromide-induced damage included STAT1-IL12-mediated inflammation, NFEmbedded ImageB-mediated inflammation and apoptosis pathways (Figure 6A), and critical apoptosis-related components in the kidney pathway (Figure 6B). Lastly, Gene Ontology (GO) analysis highlighted that the most relevant category for EGCG’s effects on iopromide-induced nephrotoxicity was the nitric oxide mediated signal transduction, followed by response to hydrogen peroxide, cellular response to oxidative stress, response to oxidative stress and other categories related to antioxidant signaling (Figure 7).

Figure 4.
Figure 4.

Volcano plot of whole-transcriptome sequencing analysis of EGCG (200 μM)-treated iopromide (50 mgI/ml)-injured HEK-293 cells.

Figure 5.
Figure 5.

The ingenuity canonical pathways of whole-transcriptome sequencing analysis of EGCG (200 μM)-treated iopromide (50 mgI/ml)-injured HEK-293 cells.

Figure 6.
Figure 6.

Network depicting associations among various genes of the anti-inflammatory pathway (A) and apoptosis of kidney pathway (B), by IPA analysis of whole-transcriptome sequencing analysis of EGCG (200 μM)-treated iopromide (50 mgI/ml)-injured HEK-293 cells.

Figure 7.
Figure 7.

Biological process (BP) of whole-transcriptome sequencing analysis of EGCG (200 μM)-treated iopromide (50 mgI/ml)-injured HEK-293 cells by Gene Ontology (GO) analysis. The top four relevant categories for EGCG’s effects on iopromide-induced nephrotoxicity was the nitric oxide mediated signal transduction, response to hydrogen peroxide, cellular response to oxidative stress, and response to oxidative stress. These categories are the only four with p-value <0.005.

Validation of ROS production and antioxidant capacity induced by EGCG. Finally, we demonstrated that treatment with 50 mgI/ml iopromide significantly increased ROS, and this effect was effectively mitigated by co-treatment with EGCG (Figure 8). As anticipated, EGCG exhibited a dose-dependent antioxidant effect in HEK-293 cells, as evidenced by the DPPH scavenging assay (Figure 9).

Figure 8.
Figure 8.

Effect of intracellular ROS of EGCG-treated iopromide-injured HEK-293 cells. HEK-293 cells were treated with iopromide (50 mgI/ml) and/or EGCG (100 and 200 μM), and intracellular ROS was measured by the DCFH-DA fluorescence probe. Results were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test; ***p<0.001 and ###p<0.001.

Figure 9.
Figure 9.

Effect of antioxidant activity of EGCG-treated iopromide-injured HEK-293 cells. HEK-293 cells were treated to iopromide (50 mgI/ml) and/or EGCG (100 and 200 μM), and antioxidant activity was measured by the DPPH radical scavenging activity. Results were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test; ***p<0.001 and ###p<0.001.

Discussion

With advancements in CT technology, the role of contrast media remains crucial. Therefore, investigating potential organ and tissue toxicity and identifying effective antidotes could significantly enhance patient quality of life. Our previous work established a model for studying iopromide-induced renal injury using the HEK-293 cell line, a human kidney cell line (33). From this work, we observed that co-treatment with 100 and 200 μM EGCG effectively reversed the reduction in cell viability induced by 50 mgI/ml iopromide over 48 h (Figure 2). Additionally, EGCG co-treatment mitigated the iopromide-induced DNA strand breaks and reduced caspase-3 activation (Figure 3). Bioinformatics signaling analysis highlighted the pivotal roles of oxidative stress, antioxidant signaling and anti-inflammatory pathways in EGCG’s protective effects against iopromide-induced nephrotoxicity (Figure 4, Figure 5, Figure 6, Figure 7). We further validated the changes in ROS levels and antioxidant capacity in HEK-293 cells (Figure 8 and Figure 9). Collectively, our findings provided the first robust evidence supporting the use of EGCG to counteract iopromide-induced renal cell damage.

EGCG offers several notable benefits. Firstly, it is commonly found in a variety of natural plants (21, 22, 42). Secondly, it is relatively inexpensive (43-45). Thirdly, EGCG is generally well-tolerated by the human body, with no or minimal toxicity (46-48). Fourthly, it does not exhibit significant interactions with other substances (49-51). Furthermore, EGCG provides protective effects for multiple organs (52-55). Notably, EGCG surpasses other phenolic compounds in terms of clearance efficiency (56-58). The primary limitation of EGCG is its rapid metabolism and relatively low bioavailability (59). Oral intake can achieve serum levels above 1 μM, with peak concentrations occurring between 1.3 and 2.2 h before declining (60). Chow et al. also evaluated the safety and kinetics of EGCG and decaffeinated green tea extract (61). Their studies focused on single doses, while continuous or prolonged consumption of tea can improve bioavailability with only minor gastrointestinal side effects (61). EGCG is also largely non-toxic to kidney cells (Figure 1). From a translational perspective, assessing systemic effects from in vitro studies on cultured cell lines presents challenges. EGCG can mitigate the production of reactive oxygen and carbonyl species through multiple mechanisms, including suppressing precursor substance generation, disrupting formation conditions, and forming stable adducts.

There is increasing evidence regarding the mechanisms through which green tea and EGCG exert protective effects against oxidative stress, including their role in mitigating metabolic dysfunction, inflammatory processes, fibrogenic responses, and tumor initiation. Key signaling molecules, such as NRF2, AMPK, SIRT1, NF-Embedded ImageB, and TGF-β are notably involved in the hepatoprotective effects of green tea and EGCG (62). This study identified numerous molecules engaged in maintaining redox homeostasis (Figure 4, Figure 5, Figure 6, Figure 7), a critical balance that involves preventing excessive ROS production and facilitating ROS scavenging through the antioxidant defense system. Both oxidant and antioxidant signaling are fundamental to redox homeostasis (63). Future research should focus on elucidating the mechanisms underlying renal cytotoxicity and developing targeted treatment strategies. Potential areas for investigation include apoptosis, autophagy, immunology, and epigenomics. Previously, our team has demonstrated that treatment of 50-200 mgI/ml iopromide would induce HEK-293 cells undergo apoptosis and autophagy simultaneously (33). In the current study, we verified the relative results, and demonstrated that EGCG was capable of reverse the iopromide-induced apoptosis in HEK-293 cells. In 2020, Gu and colleagues showed that AdipoRon, the agonist of adiponectin receptors, was capable of protecting Sprague-Dawley (SD) rats from iopromide-induced renal injury (64). The main pathways involved in drugs against iopromide-induced damage of Gu’s finding in animal models were similar, highlighting the importance of oxidative stress and inflammation pathways. In the literature, EGCG has been reported to be capable of inducing triple negative breast cancer cell lines (MDA-MB-157, MDA-MB-231, and HCC1806 breast cancer cells) to undergo apoptosis (65). However, the dosage of treating protocol is not the same as ours (5 μM versus 50 μM). Most possibly, there is a different responsiveness for normal cells and cancer cells. This critical point is worthy of validation.

In this study, EGCG demonstrates a potent antioxidant effect in mitigating iopromide-induced renal toxicity. EGCG may neutralize ROS directly or act indirectly by inhibiting ROS-generating enzymes or chelating pro-oxidant metal ions (66). Its antioxidant activity was further validated by its ability to scavenge DPPH radicals (Figure 9), which aligns with previous literature (67). The observed increase in antioxidant enzymes, such as SOD, catalase, and GSH-Px, corroborates findings from earlier studies (68-70). Three key pathways are prominently involved in EGCG’s protection against iopromide-induced cytotoxicity. The first is the NF-Embedded ImageB-related pathway. EGCG has been shown to inhibit ERK1/2, p38 MAPK, and NF-Embedded ImageB pathways in cardiomyocytes (71). The suppression of NF-Embedded ImageB by EGCG leads to anti-inflammatory and antitumor effects (72, 73), as NF-Embedded ImageB regulates the synthesis of pro-inflammatory cytokines, such as TNF-β and IL-1β, and influences cell growth (74). Unexpectedly, STAT3, which is also critical for tumor proliferation and invasion, was not predicted to be involved in EGCG’s effect against iopromide (Figure 6A). In contrast, the STAT1-related pathway emerged as a major mechanism by which EGCG counters iopromide-induced cytotoxicity (Figure 6A). Although the precise mechanisms of STAT1 involvement remain to be fully elucidated, it is known that EGCG can inhibit STAT1 activation and reduce levels of high mobility group box 1 (HMGB1), a redox-sensitive pro-inflammatory nuclear protein associated with sepsis (75, 76). The third major pathway implicated in EGCG’s protective effect is the ERK1/2-related pathway (Figure 6A). Recent studies have shown that EGCG can induce up-regulation of the p38 MAPK, ERK, and JNK signaling pathways (77). Additionally, EGCG has been reported to mitigate oxidative stress and prevent antioxidant depletion by inhibiting ERK1/2, p38 MAPK, and NF-Embedded ImageB pathways (71). Other molecules predicted to be involved in apoptosis induction in kidney cells, including DDIT3, HMOX1, CEBPB, and C5AR1 (Figure 6B), warrant further investigation to clarify their roles in EGCG’s protection against iopromide-induced cytotoxicity.

Conclusion

In summary, this study is the first to demonstrate that EGCG can counteract iopromide-induced renal cytotoxicity through a combination of bioinformatics predictions and experimental validation. The mechanisms underlying this protective effect appear to involve not only the reduction of oxidative stress but also the modulation of inflammatory responses and apoptotic pathways. Notably, the ERK1/2, STAT1, and NF-Embedded ImageB pathways are prominently involved. Further research is needed to confirm EGCG’s renal protective effects, particularly in the context of contrast agents like iopromide. This study offers a new platform for exploring EGCG’s efficacy beyond kidney epithelial cell lines, potentially facilitating its translation into clinical applications.

Acknowledgements

The present study was supported by the project supervised by Tsai in Shin-Kong Wu Ho-Su Memorial Hospital (grant no. 2022SKHDR031). The authors appreciate the special help and offer for using the Medical Research Core Facilities to perform experiments under Mr. Dai’s supervision.

Footnotes

  • Authors’ Contributions

    Research design: Tsai YF, Yang JS and Chang WS; experimental design, organization and conduction: Shih HY, Yang JS, Chang WS, Juan YN and Tsai CW; statistical analysis: Yang JS, Shih HY, Bau DT and Tsai CW; data clearance and validation: Shih HY, Yang JS, Bau DT and Chang WS; article writing: Tsai YF, Bau DT, Yang JS and Chang WS; correction of manuscript: Tsai YF, Shih HY, Yang JS, Juan YN, Tsai CW, Bau DT and Chang WS, review and revision: Yang JS, Chang WS and Bau DT.

  • Conflicts of Interest

    The Authors declare no conflicts of interest regarding this study.

  • Received July 23, 2024.
  • Revision received August 21, 2024.
  • Accepted August 29, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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