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. 2024 Mar 3;38(2):630–639. doi: 10.21873/invivo.13482

Cisplatin Induces Kidney Cell Death via ROS-dependent MAPK Signaling Pathways by Targeting Peroxiredoxin I and II in African Green Monkey (Chlorocebus aethiops sabaeus) Kidney Cells

HUI-NA ZHANG 1,#, WAN-QIU XIAO 1,#, DONG HUN LEE 2,#, NAN LI 1, YAO-YUAN FENG 1, TING SU 1, HAN-YU GU 1, IJOO YOON 3,4, HAIYOUNG JUNG 3,4, KYUNG HO LEE 3,5, HEE JUN CHO 3,6, YING-HAO HAN 1, HU-NAN SUN 1, TAEHO KWON 3,7
PMCID: PMC10905483  PMID: 38418129

Abstract

Background/Aim

Cisplatin [cis-diamminedichlo-roplatinum(II), CDDP] is a widely used and effective antitumor drug in clinical settings, notorious for its nephrotoxic side effects. This study investigated the mechanisms of CDDP-induced damage in African green monkey kidney (Vero) cells, with a focus on the role of Peroxiredoxin I (Prx I) and Peroxiredoxin II (Prx II) of the peroxiredoxin (Prx) family, which scavenge reactive oxygen species (ROS).

Materials and Methods

We utilized the Vero cell line derived from African green monkey kidneys and exposed these cells to various concentrations of CDDP. Cell viability, apoptosis, ROS levels, and mitochondrial membrane potential were assessed.

Results

CDDP significantly compromised Vero cell viability by elevating both cellular and mitochondrial ROS, which led to increased apoptosis. Pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) effectively reduced CDDP-induced ROS accumulation and subsequent cell apoptosis. Furthermore, CDDP reduced Prx I and Prx II levels in a dose- and time-dependent manner. The inhibition of Prx I and II exacerbated cell death, implicating their role in CDDP-induced accumulation of cellular ROS. Additionally, CDDP enhanced the phosphorylation of MAPKs (p38, ERK, and JNK) without affecting AKT. The inhibition of these pathways significantly attenuated CDDP-induced apoptosis.

Conclusion

The study highlights the involvement of Prx proteins in CDDP-induced nephrotoxicity and emphasizes the central role of ROS in cell death mediation. These insights offer promising avenues for developing clinical interventions to mitigate the nephrotoxic effects of CDDP.

Keywords: Cisplatin, nephrotoxicity, African green monkey kidney (Vero) cells, peroxiredoxin, reactive oxygen species, MAPKs

Cisplatin [cis-diamminedichloroplatinum(II), CDDP] is a cornerstone chemotherapeutic agent utilized extensively to treat a variety of solid malignancies, including testicular, ovarian, and lung cancers, owing to its remarkable antitumor potency (1). Its mechanism of action is multifaceted, involving mitochondrial dysfunction, oxidative stress, and the initiation of various signal transduction pathways, which collectively lead to apoptosis mediated by mitochondria (2,3). However, the emergence of drug resistance and the development of severe renal complications remain significant challenges (4).

It is established that CDDP preferentially accumulates in proximal tubular epithelial cells, a phenomenon attributed to the specific distribution of CDDP transporters that facilitate its entry during glomerular filtration and tubular secretion (5). Within the renal cells, CDDP undergoes aquation, replacing its chlorine atoms with water molecules, which disrupts mitochondrial function by altering membrane transporter expression. This leads to an overproduction of reactive oxygen species (ROS), instigating oxidative stress and inflammatory responses, culminating in cellular apoptosis (6,7).

Reactive oxygen species (ROS) are crucial intracellular messengers involved in the regulation of cell proliferation, differentiation, apoptosis, metabolism, and migration (8). Elevated CDDP doses have been linked to substantial ROS generation, activating apoptosis-related proteins and disturbing mitochondrial membrane potential, resulting in apoptosis (9).

Peroxiredoxins (Prxs) are antioxidant enzymes that play a vital role in scavenging intracellular ROS (10). They are integral to cellular processes such as signal transduction, and tumor cell behaviors, such as proliferation, migration, and apoptosis (11,12). Among the members of the Prxs family, Prx I and Prx II are recognized for their antioxidant capabilities. They are essential in maintaining the cellular redox state and preventing apoptosis under both standard and oxidative stress conditions (13,14), The suppression of Prx I has been associated with increased ROS and the subsequent death of esophageal cancer cells (15), whereas Prx II has been implicated in modulating oxidative stress-induced apoptosis in gastric cancer cells (16). This evidence suggests that Prx I and Prx II could be crucial in regulating apoptosis induced by oxidative stress.

In our current study, we have applied CDDP to induce apoptosis in African green monkey kidney (Vero) cells to examine the roles of Prx I and Prx II in this context. We conducted MTT assays, fluorescence microscopy, and western blot analyses to evaluate cell viability, apoptosis, cellular and mitochondrial ROS levels, mitochondrial damage, and the expression of apoptosis-related proteins. Our research aimed to elucidate the roles of Prx I and Prx II in oxidative stress-induced apoptosis in kidney cells, thereby laying the groundwork for potential therapeutic interventions.

Materials and Methods

Reagents and chemicals. Cisplatin (CDDP) was obtained from Yisheng (Shanghai Yisheng Biological, Shanghai, PR China). Fetal bovine serum (FBS) and Dulbecco’s modified Eagle’s medium (DMEM) were procured from Hyclone (General Electric Healthcare Life Sciences, Mississauga, Canada). Penicillin and streptomycin (P/S) were sourced from Solarbio (Solarbio Life Sciences, Beijing, PR China).

Cell culture. African green monkey kidney (Vero) cells, provided by Procell Life Science & Technology Co., Ltd., (Wuhan, PR China), were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) enhanced with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (P/S). The cells were incubated at 37˚C in a humidified atmosphere containing 5% CO2, during their logarithmic phase of growth.

Cell viability assay. The viability of Vero cells post-CDDP exposure was determined using the MTT assay, with reagents from Sigma-Aldrich (St. Louis, MO, USA). Cells were plated at a density of 4×103 cells/well in 96-well plates and treated with CDDP at concentrations of 0, 2.5, 5, 10, and 20 μM for 24 or 48 h. Post-treatment, MTT solution (0.5 mg/ml) was added, and the plates were incubated for 2 h at 37˚C in a 5% CO2 environment. The resultant formazan crystals were solubilized in DMSO, and the absorbance was measured at 570 nm using a microplate reader (Molecular Devices, Sunnyvale, CA, USA).

Detection of apoptosis. Apoptosis was assessed in Vero cells seeded at 6×104 cells/well in 24-well plates and treated with CDDP for 48 h. Apoptotic cells were identified using the Annexin V-FITC/PI or Annexin V-PE detection kit from BD Biosciences (Franklin Lake, NJ, USA), according to the manufacturer’s instructions. The stained cells were then analyzed with an EVOS®xl core cell culture microscope (Advanced Microscopy Group, Paisley, UK).

Cellular and mitochondrial ROS level detection. To quantify intracellular ROS production, Vero cells, seeded at 6×104 cells/well in 24-well plates and treated with CDDP for 48 h, were stained with Dihydroethidium (DHE) from Beyotime Biotechnology (Shanghai, PR China). Mitochondrial ROS levels were specifically measured using MitoSOX staining provided by Thermo Fisher Scientific (Waltham, MA, USA). Fluorescence microscopy was employed to visualize the staining results.

Mitochondrial membrane potential changes detection. Vero cells, at a density of 6×104 cells per well, were seeded into 24-well plates and treated with CDDP for 48 h. Changes in the mitochondrial membrane potential were assessed using the JC-1 fluorescent probe (Thermo Fisher Scientific). Fluorescence microscopy was utilized to observe and document the resulting changes.

Western blot analysis. Cellular proteins were lysed, quantified, and then subjected to SDS-PAGE using a 12% gel, with each well loaded with 10 μg of protein. The proteins were then electrotransferred onto nitrocellulose membranes (Millipore, Boston, MA, USA). Membranes were probed with primary antibodies against cleaved caspase-3, cleaved caspase-9, Bax, Bcl-2, β-actin, Prx I-VI, phosphorylated and total AKT, ERK, JNK, and p38 (Santa Cruz Biotechnology, Dallas, TX, USA), all diluted to 1:1,000, and incubated overnight at 4˚C with agitation. After incubation, membranes were washed with Tris-buffered saline containing 0.2% Tween 20 TBS buffer (TBST), and incubated with HRP-conjugated secondary antibodies (Sigma-Aldrich) for 1 h at room temperature. Post-washing, protein bands were visualized using a chemiluminescence detection system (Amersham, Buckinghamshire, UK), as per the manufacturer’s protocol.

Statistical analysis. The data are expressed as the mean±standard deviation (SD) from three independent experiments. Statistical analysis was conducted using SPSS 19.0 software (SPSS Inc., Chicago, IL, USA). A two-way analysis of variance (ANOVA) was employed to assess significant differences between the treatment groups, with a significance level set at p<0.05.

Results

Effect of CDDP on Vero cell viability and apoptosis. To elucidate the effects of CDDP on Vero cell viability, cells were treated with increasing concentrations of CDDP (2.5, 5, 10, 20 μM) over various time points (0, 24, 48 h). Cell survival was quantitatively measured via the MTT assay. A dose- and time-dependent decrease in cell viability was observed, with higher concentrations and longer exposure times significantly reducing cell survival (Figure 1A). To determine whether the decrease in cell viability was due to CDDP-induced apoptosis, Vero cells were exposed to 0, 5, 10, and 20 μM of CDDP for 48 h. Apoptosis was assessed by fluorescence microscopy following Annexin V-FITC and PI staining, and the expression of apoptosis-related proteins was analyzed using western blot. An increase in Annexin V-FITC and PI fluorescence intensity correlated with higher CDDP concentrations, indicative of increased apoptotic activity. The western blot analysis corroborated these findings, revealing an up-regulation of cleaved Caspase-3, cleaved Caspase-9, and Bax proteins, alongside a down-regulation of Bcl-2 expression, further confirming that CDDP induces apoptosis in Vero cells (Figure 1B and C).

Figure 1. Cisplatin (CDDP)-induced apoptosis in Vero cells. (A) Evaluation of Vero cell survival using MTT assay following treatment with different CDDP concentrations (0, 2.5, 5, 10, 20 μM) for 24 and 48 h. (B) Assessment of apoptosis levels in CDDP-treated Vero cells using Annexin V-FITC and PI staining. (C) Analysis of apoptosis-related protein levels in Vero cells treated with CDDP using western blot.

Figure 1

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Effects of CDDP on ROS levels, mitochondrial damage, Prxs protein expression, and apoptosis in Vero cells. Our investigation into the role of CDDP in modulating ROS levels utilized Dihydroethidium (DHE) as a fluorescent marker. The intensity of DHE fluorescence increased in a dose-dependent manner with CDDP treatment, indicating elevated intracellular ROS levels (Figure 2A). Mitochondrial ROS were similarly assessed with MitoSOX staining, which also showed enhanced fluorescence correlating with higher CDDP doses (Figure 2B). Mitochondrial integrity, judged by membrane potential using the JC-1 probe, was compromised upon CDDP treatment. A dose-dependent decline in JC-1 fluorescence suggested a loss of mitochondrial membrane potential (Figure 2C). Furthermore, we examined the effect of CDDP on the expression of Prxs proteins and observed a marked decrease in Prx I and Prx II levels in response to rising concentrations and exposure times to CDDP (Figure 2D and E). This suggests a CDDP-mediated alteration in Prxs protein homeostasis. In addition, the regulatory function of Prx I and Prx II in apoptosis was probed by treating cells with Conoidin A, a Prx inhibitor. Post-treatment analysis revealed an increased apoptotic response when compared to CDDP treatment alone, as evidenced by enhanced Annexin V-FITC/PI fluorescence. Western blot analysis supported this finding, showing increased levels of cleaved Caspase-3, cleaved Caspase-9, and Bax, alongside diminished Bcl-2 expression in the Conoidin A group (Figure 2F and G). These results collectively highlight the protective role of Prx I and Prx II against CDDP-induced apoptosis.

Figure 2. Effects of cisplatin (CDDP) on reactive oxygen species (ROS) levels, mitochondrial damage, peroxiredoxins (Prxs) protein expression, and apoptosis following Conoidin A treatment in Vero cells. (A) Assessment of ROS levels in CDDP-treated Vero cells using DHE and Hoechst staining. (B) Examination of mitochondrial ROS levels in CDDP-treated Vero cells through Mito SOX and Hoechst staining. (C) Detection of CDDP-induced mitochondrial damage in Vero cells using JC-1 staining. (D) Analysis of Prxs protein levels in Vero cells treated with various concentrations of CDDP (0, 2.5, 5, 10, 20 μM) for 48 h using western blot. (E) Examination of Prxs protein levels in Vero cells treated with 20 μM CDDP for different time periods (0, 3, 6, 12, 24, 48 h) using western blot. (F) Assessment of the impact of Conoidin A treatment on CDDP-induced apoptosis in Vero cells using Annexin V-FITC and PI staining. (G) Analysis of apoptosis-related protein levels in Vero cells after Conoidin A treatment using western blot.

Figure 2

Figure 2

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Effects of CDDP on ROS levels, mitochondrial damage, and apoptosis in Vero cells following NAC pretreatment. In examining the link between ROS accumulation and CDDP-induced apoptosis, we pretreated Vero cells with N-acetylcysteine (NAC) at 5 and 10 mM for 30 min prior to CDDP exposure. Dihydroethidium (DHE) staining indicated a substantial decrease in intracellular ROS levels post-NAC pretreatment, as reflected by diminished fluorescence intensity (Figure 3A). This effect extended to mitochondrial ROS, where MitoSOX staining revealed a significant decrease in fluorescence, suggesting lowered mitochondrial ROS levels after NAC pretreatment (Figure 3B).

Figure 3. Effects of cisplatin (CDDP) on reactive oxygen species (ROS) levels, mitochondrial damage, and apoptosis in Vero cells following N-acetyl-L-cysteine (NAC) pretreatment. (A) Evaluation of ROS levels in CDDP-treated Vero cells following pretreatment with different NAC concentrations (5 and 10 mM) using dihydroethidium (DHE) and Hoechst staining. (B) Examination of mitochondrial ROS levels in CDDP-treated Vero cells following pretreatment with different NAC concentrations (5 and 10 mM) through Mito SOX and Hoechst staining. (C) Detection of CDDP-induced mitochondrial damage in Vero cells following pretreatment with different NAC concentrations (5 and 10 mM) using JC-1 staining. (D) Assessment of apoptosis levels in CDDP-treated Vero cells following pretreatment with different NAC concentrations (5 and 10 mM) using Annexin V-FITC and PI staining. (E) Analysis of apoptosis-related protein levels in Vero cells following pretreatment with different NAC concentrations (5 and 10 mM) using western blot. (F) Quantitative analysis of protein expression levels. (Statistical significance denoted as *p<0.05, **p<0.01, **p<0.001).

Figure 3

Figure 3

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Mitochondrial integrity, assessed by JC-1 staining for membrane potential, showed notable preservation in the NAC-pretreated groups, demonstrating increased mitochondrial membrane potential relative to cells treated with CDDP alone (Figure 3C).

Furthermore, to establish the relationship between ROS and apoptosis, apoptosis levels and protein expression were evaluated following NAC pretreatment. Fluorescence micro-scopy using Annexin V-FITC/PI staining showed a reduction in apoptosis in the NAC-pretreated cells (Figure 3D). Western blot analysis supported this observation, showing a decrease in the expression of pro-apoptotic proteins cleaved Caspase-3, cleaved Caspase-9, and Bax, and an increase in anti-apoptotic Bcl-2 expression in comparison to the CDDP-only treatment (Figure 3E). Collectively, these results underscore the role of increased ROS levels in CDDP-induced apoptosis and establish NAC’s efficacy in mitigating oxidative stress and consequent cell death in Vero cells.

Inhibition of MAPK signaling pathways rescues CDDP-induced apoptosis in Vero cells. To elucidate the regulatory role of CDDP on apoptosis via signaling pathways in Vero cells, we focused on the expression of proteins involved in MAPK and AKT pathways. Western blot analysis revealed a notable elevation in the phosphorylation of ERK, JNK, and p38 proteins after extended CDDP treatment, while phosphorylated AKT levels did not exhibit significant changes (Figure 4A). This pattern suggests an activation of the MAPK signaling pathway by CDDP. To determine if the MAPK pathway facilitated CDDP-induced apoptosis, cells were treated with specific MAPK inhibitors. Annexin V staining and subsequent western blot analysis were employed to evaluate the cellular response. The presence of MAPK inhibitors resulted in a marked decrease in apoptosis, as indicated by reduced Annexin V binding. Concurrently, western blot analysis showed a decrease in the levels of pro-apoptotic proteins cleaved caspase-3, cleaved caspase-9, and Bax, and an increase in anti-apoptotic Bcl-2 expression (Figure 4B and C). These changes illustrate that inhibition of the MAPK signaling pathway can significantly attenuate CDDP-induced apoptosis. The data thus support the hypothesis that CDDP triggers apoptosis in Vero cells predominantly through the MAPK signaling cascade, and that modulation of this pathway could be a viable approach to mitigate CDDP-induced cellular apoptosis.

Figure 4. Inhibition of MAPK signaling pathways rescues cisplatin (CDDP)-induced apoptosis in Vero cells. (A) Analysis of AKT protein and MAPK family expression levels in Vero cells treated with 20 μM CDDP for different time periods (0, 3, 6, 12, 24, 48 h) using western blot. (B) Assessment of the impact of MAPK inhibitors on apoptosis levels in CDDP-treated Vero cells using Annexin V-FITC and PI staining. (C) Analysis of apoptosisrelated protein levels in Vero cells treated with MAPK inhibitors using western blot.

Figure 4

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Discussion

CDDP has established efficacy against a range of solid tumors, yet its clinical application is often constrained by its nephrotoxicity (17,18). The apoptosis of renal cells, a critical outcome of CDDP-induced nephrotoxicity, has garnered considerable research attention (19). It is well-documented that CDDP can provoke mitochondrial dysfunction and oxidative stress, exacerbated by the dysregulation of endogenous antioxidant enzymes (20). ROS, which include a variety of highly reactive oxygen-containing entities, are integral to the cellular oxidative stress response (21,22). Pathological overproduction of ROS can lead to cellular turmoil, manifesting as oxidative stress and mitochondrial damage (23).

Our investigation confirms that exposure of African green monkey kidney Vero cells to CDDP triggers ROS accumulation, mitochondrial dysfunction, and ensuing apoptosis. We have demonstrated that N-acetylcysteine (NAC), an antioxidant and ROS scavenger, can significantly attenuate these effects (24). Pretreatment with NAC curbed CDDP-induced ROS accumulation and mitochondrial ROS, leading to increased mitochondrial membrane potential and reduced apoptosis, thereby reinforcing the critical role of ROS in mediating CDDP-induced apoptosis in Vero cells. Additionally, the MAPK signaling pathway, which governs cell proliferation, differentiation, apoptosis, and inflammation, has been implicated in the pathogenesis of various diseases when dysregulated (25). Activation of ERK, JNK, and p38 MAPK by ROS is known to affect cellular responses, including apoptosis (26,27). We observed marked phosphorylation of these MAPKs in response to CDDP, indicating their involvement in the apoptotic process induced by the drug in Vero cells. Prxs, particularly Prx I and Prx II, are crucial antioxidants that modulate intracellular ROS levels and redox signaling (28). Our results suggest a protective role for Prx I and Prx II over-expression against CDDP-induced apoptosis, pointing to their potential as therapeutic targets.

Conclusion

In conclusion, our study elucidated the mechanism of CDDP-induced apoptosis in African green monkey kidney Vero cells, implicating a ROS-dependent MAPK signaling pathway and the regulatory role of Prx I and Prx II expression. These insights provide promising directions for developing targeted treatments for nephrotoxicity and advance our understanding of the interplay between Prx I, Prx II, and CDDP-induced apoptosis, establishing a theoretical basis for future interventions.

Conflicts of Interest

These Authors declare no conflicts of interest in relation to this study.

Authors’ Contributions

HNZ, WQX, DHL, HNS, and TK: conceptualization (equal); data curation (lead); formal analysis (lead); investigation (lead); methodology (equal); visualization (lead); writing−original draft (equal); writing−review & editing (supporting). NL, YYF, TS, HYG, IY, HJ, KHL, HJC, and YHH: data curation (equal); formal analysis (equal); investigation (equal); methodology (supporting); writing−review & editing (equal). All Authors read and approved the final manuscript.

Acknowledgements

This work was supported by the Natural Science Foundation of Heilongjiang Province of China (LH2022C060). This study was financially supported by Chonnam National University (Grant number: 2022-2731), the National Research Foundation of Korea (RS-2023-00251463), a Korea Basic Science Institute grant (H, J, C., CC202308) and the KRIBB Research Initiative Program (KGM5162423).

Funding

This research was supported by the National Research Council of Science & Technology (NST) grant by the Korea government (MSIT) (No. CCL23041-100, KRIBB-NTM2562311).

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