Eleutherococcus senticosus Alleviates Aristolochic-Acid-Induced Acute Kidney Damage by Inhibiting the NLRP3/IL-1β Signaling Pathway in Mice

• Abstract
• Introduction
• Results
• Discussion
• Materials and Methods
• Animal experiments
• Modeling acute kidney injury in mice and pharmacological intervention
• SCr and Blood Urea Nitrogen (BUN) detection
• Detection of kidney index and histological changes
• Western blot analysis
• Enzyme-linked immunosorbent assay
• Statistical analysis
• Declarations
• Ethics approval and consent to participate
• Availability of data and materials
• Contributorsʼ Statement
• References

Abstract

Eleutherococcus senticosus (ES) exerts various pharmacological effects, including renoprotection in a rat model of renal ischemia-reperfusion injury. However, the mechanisms of these effects remain unclear. Therefore, we investigated the effects and mechanisms of ES on aristolochic acid (AA)-induced acute kidney injury in mice. The experimental mice were divided into the control group, the model group (AA-induced acute kidney injury model), the model + ES group (Eleutherococcus senticosus boiled-free granules treated by gavage for two weeks), the model + fasudil group (fasudil administered intraperitoneally for three days), and the model + ES + fasudil group. After AA intervention in normal mice, the expression of ASC and NLRP3 and the levels of IL-1β, IL-18, and TNF-α were significantly elevated in mouse renal tissues (P < 0.05). However, AA-induced renal dysfunction was ameliorated by both ES and fasudil, which was confirmed by the decrease in serum creatinine and blood urea nitrogen levels, as well as by renal histopathological abnormalities such as renal tubule dilation and tubular formation. In addition, the inflammatory response of AA-induced renal inflammation was inhibited by both ES and fasudil, and the expression of ASC and NLRP3 and the levels of IL-1β, IL-18, and TNF-α were significantly higher in mouse renal tissues after the treatment of either ES or fasudil (P < 0.05). ES may be a potential treatment agent for aristolochic-acid-triggered nephropathy, with inhibition of the NLRP3/IL-1β as one plausible underlying mechanism.

Introduction

The rate of aristolochic acid nephropathy (AAN) caused by Aristolochia sinensis herbal medicines is potentially increasing, and the incidence of AAN is much higher than initially thought, especially in Asia [1]. AAN can cause acute kidney damage and is associated with a potential progression of renal fibrosis [2]. Currently, experiments in vivo and in vitro have shown that the following five main factors are involved in the development of AAN: (1) endoplasmic reticulum stress and damage [3], (2) oxidative stress damage [4], (3) impaired mitochondrial function [5], (4) immune-mediated inflammatory mechanisms [6], and (5) renal tubular epithelial cell transdifferentiation [7]. Proximal tubular epithelial cells are the main target of aristolochic-acid-induced kidney injury [8], and studies on these cells have revealed that aristolochic acid promotes the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing CARD (ASC), enhanced caspase-1 secretion, and significantly increased the secretion of the inflammatory factors interleukin (IL)-1β and IL-18 in a dose- and time-dependent manner, suggesting that aristolochic acid activates NLRP3 inflammatory vesicles in renal tubular epithelial cells [9]. A large number of studies have confirmed the role of NLRP3 in various renal diseases, and it is believed that blocking the activation of pathologic inflammatory vesicles may be an essential approach for the treatment of renal diseases in the future [10], [11], so that inhibiting the activation of NLRP3 may contribute to decreasing the occurrence and development of AAN.

Eleutherococcus senticosus (Rupr. and Maxim.; ES) Harms (Araliaceae) is known for its effectiveness in traditional Chinese medicine in improving the functionality of the neurological system, heart, gastrointestinal tract, and kidneys [12]. ES has the function of antioxidant activity, scavenging oxygen free radicals, inhibiting inflammation, and enhancing the antioxidant function of the organism [13], [14]. In the study of ES on the renal ischemia-reperfusion injury model in rats, it was found that ES has a protective effect on the kidneys, which can increase the activity of superoxide dismutase (SOD) in renal tissues, enhance the antioxidant effect, attenuate oxidative damage, inhibit the activity of tumor necrosis factor-α (TNF-α), attenuate inflammatory damage, reduce the damage of inflammation, reduce the level of serum creatinine (SCr), and reduce the pathological changes; as well, the renal function is obviously improved [15], [16]. This study aimed to ascertain the renoprotective impact of ES on acute renal injury induced by aristolochic acid and to explore the mechanisms that are involved.

Results

The pathology of congestion and hypertrophy in the renal organs was generally indicated by an increase in the Kidney Index in mice, which was considerably greater (P < 0.05) in the model group when compared to the control ([Table 1]). The miceʼs kidneys were softer, paler, and larger in size than those of the control group ([Fig. 1 b]–c). The Kidney Index significantly decreased (P < 0.05) after two weeks of ES treatment or three days of fasudil treatment ([Table 1]), and both miceʼs kidneys were more bright red in color than those of the AAN model group ([Fig. 1 d]–f). Currently, several studies have found that AA can cause abnormal renal function in rodents [17], [18]. The SCr and BUN of mice in the AAN model group were significantly higher (P < 0.001) than those in the control group, suggesting that the renal function of mice was significantly impaired. After two weeks of ES treatment and/or three days of fasudil treatment, the SCr and BUN in the treated group decreased significantly (P < 0.001) compared with the AAN model group ([Fig. 2 g]–h), suggesting that the impaired renal function was improved.

AAN is mainly responsible for proximal renal tubular dysfunction and structural damage [19]. In our investigation, in comparison to the control group ([Fig. 2 a]), the AAN model group exhibited distinct renal tubular protein pattern, swollen, and congested renal tubules, inflammatory cell infiltration in the renal interstitium ([Fig. 2 b]), extensive tubular dilatation, and interstitial edema ([Fig. 2 c]). The renal tubular injury score of mice was significantly higher than that of the control group (P < 0.001) ([Fig. 2 i]). Following two weeks of ES treatment, some renal tubules showed dilation, but the number was lower than that of AAN ([Fig. 2 d]). After three days of fasudil intervention, most renal tubules returned to normal, with only a few small areas of dilation, and the number was significantly lower than that of the model group ([Fig. 2 e]). With simultaneous treatment of fasudil and ES, most renal tubules returned to normal, with only scattered individual tubular dilation observed ([Fig. 2 f]). The renal tubular damage scores of mice exhibited a considerable reduction (P < 0.001) following treatment with ES or fasudil ([Fig. 2 i]).

Inflammation plays a crucial role in the pathophysiology of AAN [1]. We thus investigated the effects of AA on inflammatory vesicles (NLRP3 and ASC) and inflammatory factors (IL-1β, TNF-α, and IL-18) in mice. What we discovered was that AA significantly increased the WB expression of inflammatory vesicles (NLRP3 and ASC) in the model group (P < 0.001) when compared to the control group ([Fig. 3 a]–b). Furthermore, the model group produced by AA had a substantial rise in the expression of inflammatory markers including IL-1β (P < 0.001), TNF-α (P < 0.001), and IL-18 (P < 0.05) ([Fig. 3 c]–e).

Discussion

In this study, ES and fasudil were found to ameliorate AA-induced damage to renal tissue structure significantly, and these effects of theirs were associated with controlling the inflammatory response of renal tissue. Our data demonstrate that ES can prevent the kidneys from developing AAN in a way that inhibits inflammation.

It is estimated that globally drug-related nephrotoxicity accounts for 26% of patients with hospital-acquired acute kidney injury (AKI), and in the community, this is 18%, and the contribution of herbal medicines to them is unclear [20]. Aristolochia is the fruit of plants of the Aristolochiaceae family. Aristolochia includes aristolochic acid, the most poisonous substance in Aristolochia L. plants, and has a significant nephrotoxic effect [21]. Even though many countries and regions have taken measures to reduce the consumption of AA, the prevalence of AAN remains high in areas where traditional medicine is prevalent [22]. It is estimated that more than 100 million people around the world are at risk of developing AAN [23]. AAN is a progressive tubulointerstitial nephritis with acute tubular damage and clinical signs of irreversible renal decompensation that, if untreated, may eventually proceed to end-stage renal disease (ESRD) [17].

NLRP3 inflammatory vesicles are composed of an NLRP3 pattern recognition receptor, articulin ASC, and caspase-1 [24]. When cells are stimulated by endogenous or exogenous danger signals, intracellular pattern recognition receptors initiate a series of signaling cascades by recognizing pathogen-associated and damage-associated molecular patterns, which promote the release of a large number of inflammatory mediators, leading to the occurrence of an inflammatory response [25]. Activation of the inflammatory vesicle NLRP3 promotes the shearing of caspase-1 precursors by protein hydrolysis, and then, the active caspase-1 further shears the pro-inflammatory cytokines IL-1β and IL-18 to mature forms that are released extracellularly [26]. It has been found that activated NLRP3 inflammatory vesicles are involved in the regulation of cellular inflammatory response, metabolism, and survival and that they play an important role in the occurrence and development of diabetic nephropathy, hypertensive nephropathy, rhabdomyolysis, interstitial fibrosis, and ischemic nephropathy. Furthermore, these results indicate that NLRP3 genetic deletion slows the development of kidney illness [27], [28]. Ding found that mature IL-1β and IL-18 were significantly reduced in kidney samples from aldosterone-injected NLRP3-/- mice, suggesting that NLRP3 deletion ameliorates tubular injury and improves renal function, as well as indicating that NLRP3 inflammatory vesicle-dependent release of mature IL-1β/IL-18 may be associated with renal tubular inflammation and injury [29]. More and more evidence demonstrates that oxidative stress, renal tubular cell apoptosis, inflammation, and fibrosis are important pathogenic processes in AAN [1], [30]. In this study, we used AA to produce a model of acute kidney injury, and as expected, the kidneys of AA-induced mice became enlarged and showed pathological changes in renal tubular protein tubular pattern, swollen and congested tubules, extensive tubular dilatation, and renal interstitial edema. In addition, the expression of NLRP3, ASC, IL-1β, TNF-α, and IL-18 in renal tissues was significantly increased in the AA-induced acute kidney injury model, which confirmed the inflammatory response in AAN.

Since ancient times, ES has been used as a Chinese herbal supplement that has the effect of dispelling wind and removing dampness, invigorating the liver and kidneys, promoting diuresis, and diminishing swelling, promoting blood circulation, and removing blood stasis, strengthening sinews and bones [31]. It is often widely used in China, Korea, Japan, and Russia for its specific pharmacological effects [32]. It was discovered that it could inhibit renal endothelin synthesis and play a treatment role for diabetic nephropathy [33] and can improve renal ischemia-reperfusion injury by inhibiting oxidative stress and inflammation in the renal tissues of rats [34]. It has been found that Rho-Kinase (ROCK) can cause proximal tubular injury and increased proteinuria [35], so fasudil, as a selective ROCK inhibitor, has been proven to contain a protective effect against renal fibrosis [36]. In this study, we noted that ES or fasudil was effective in ameliorating acute renal failure, as evidenced by the improvement of AA-induced histopathologic changes in the kidneys (e.g., tubular dilatation and tubiform formation). Results from most studies that have identified a role for herbs or their active ingredients in the treatment of kidney disease have consistently shown that inhibition of NLRP3 is associated with the protective effects of these compounds on the kidneys. Wang discovered that NLRP3 or caspase-1 deficiency could protect the kidney from injury in the AAN mouse model, implying that the NLRP3 signaling pathway may be involved in the pathogenesis of AAN [37]. Fasudil exerts its effects in the treatment of acute kidney injury by decreasing the expression level of IL-1β in a rat model [38], and its anti-inflammatory effect could be performed by inhibiting the expression level of cellular pyroptosis-associated proteins (NLRP3 and ASC) and inflammatory factors (IL-1β, TNF-α, and IL-18) [39]. Therefore, we tested the inflammatory vesicles and inflammatory factors in mouse kidneys, and we found that both ES and fasudil significantly suppressed the high expression of inflammatory factors by inhibiting the AA-induced activation of the NLRP3/IL-1β signaling pathway in mouse kidneys. These findings indicate that ES can effectively inhibit AA-induced inflammatory responses by regulating the expression of NLRP3, ASC, IL-1β, TNF-α, and IL-18. This trial demonstrated that the optimal outcomes were achieved in the group receiving the combination of ES and fasudil, surpassing those in the monotherapy group, likely attributable to the synergistic impact of ES and fasudil when administered together for enhanced therapeutic efficacy. In a rat model of acute kidney injury, oral administration of Eleutherococcus radix extract decreased nitric oxide levels and lipid peroxidation, enhanced catalase and glutathione peroxidase activities, and mitigated renal dysfunction, indicating that the scavenging of ROS is a significant mechanism by which ES prevents renal impairment [40]. Furthermore, ROS are crucial for sustaining redox balance and serve as a primary mediator in the activation of NLRP3 inflammasomes [41]. Consequently, we suspect that the inflammatory suppression of the kidney by ES in our study may be associated with redox balance.

This study successfully demonstrates for the first time the potential protective effects of ES in mitigating aristolochic-acid-induced acute kidney injury while also investigating the underlying molecular mechanisms, including the inhibition of NLRP3 inflammasome activation by ES ([Fig. 4]). This significant discovery not only augments the therapeutic potential of ES in the management of acute renal injury but also offers a novel perspective for investigating its anti-inflammatory properties.

Materials and Methods

Animal experiments

Four- to six-week-old male C57BL/6 mice (SCXK2019-0010, SPF (Beijing) BIOTECHNOLOGY Co., Ltd). The feeding grade was SPF, five mice per cage were kept in a well-ventilated room, temperature was maintained at 20 – 26 °C, relative humidity was maintained at 40 – 70%, lighting was alternated between day and night for 12 hours, and food and water were freely provided to the mice during the experiment. The fundamental parameters of our experimental animals were comparable to those outlined by Wang et al. in their investigation of the impacts of polystyrene microplastics in C57BL/6 mice [42]. The appeal animal experiments were reviewed and approved by the Laboratory Animal Ethics Committee of Jiangxi Zhonghong Boyuan Biotechnology Co., Ltd. (approval number: 2 022 081 902; approval date: August 19th, 2022). We verified that the experiments were performed in accordance with ARRIVE guidelines (https://arriveguidelines.org). We also verified that the experiments were performed in accordance with relevant guidelines and regulations.

Modeling acute kidney injury in mice and pharmacological intervention

After all mice were acclimatized for one week, the mice were randomly divided into the following (six mice per group): blank control group, model group, model + ES group, model + fasudil group, and model + ES + fasudil group. Except for the normal control group (without any intervention treatment), all mice were subjected to the construction of an acute kidney injury model. Autoclaved aristolochic acid I solution (CAS#313 – 67 – 7, Shanghai Yuanye Bio-Technology Co., Ltd) was injected intraperitoneally at 10 mg/kg and 10 mL/kg for a total of two weeks [43]. Treatment with drugs according to different experimental groups, model + ES group was as follows: Eleutherococcus senticosus boiled-free granules (primary components: Eleutherococcus senticosus, additives: dextrin, sucrose; each gram of the medication comprises approximately 5.2 mg of syringin and approximately 3.5 mg of eleutheroside E.) (CiWuJiaKeLi, Z22023372, Xiuzheng Pharmaceutical Group Changchun High Technology Pharmaceutical Co. Ltd.) at a dose of 4.92 g/kg (1 mg = 20 mg of raw drug; reference standard for concentration: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers) by gavage twice daily for two weeks [40]; model + fasudil group: fasudil (2 108 191, Tianjin Chase Sun Pharmaceutical Co., Ltd) was administered daily by intraperitoneal injection at a dose of 20 mg/kg once daily for three days [44]; model + ES + fasudil group: ES was administered by gavage at a dose of 4.92 g/kg divided twice daily for two weeks, together with fasudil administered by intraperitoneal injection at a dose of 20 mg/kg once daily for three days. The experimental process was carried out ([Fig. 1 a]); following the pharmacological intervention, the mice were euthanized, and their kidneys were promptly collected for later study.

SCr and Blood Urea Nitrogen (BUN) detection

As the experiments ended, the SCr assay kit (69 – 21 413, Wuhan Moshak Biotechnology Co., Ltd.) was used to detect the serum SCr content of mice, and the BUN test kit (69 – 21 426, Wuhan Moshak Biotechnology Co., Ltd.) was used to detection of BUN level in mice; all the above were done according to the kit instructions.

Detection of kidney index and histological changes

The body weights of mice in each group were recorded. Ten minutes passed after the mice received an intraperitoneal anesthetic injection (1% sodium pentobarbital, 70 mg/kg) before they were executed by cervical dislocation. Weights of bilateral kidneys of mice were taken, and the Kidney Index was calculated and compared for each group. Mouse kidney tissues were fixed in 4% formaldehyde, completely immersed for one day, and then routinely paraffin-embedded and sectioned. Sections were deparaffinized, dehydrated, and treated with gradient alcohol rehydration for 3 min, stained with hematoxylin (G1004, Servicebio), washed, differentiated, dehydrated with alcohol, stained with eosin (G1001, Servicebio), and dehydrated with alcohol again in a gradient, and then sealed and observed under the microscope. In addition, renal tubular damage in HE-stained sections was assessed by scoring 10 randomly selected areas of each renal tissue section at 200× magnification on the following principles: 0, 0%; 1, ≤ 10%; 2, 11 – 25%; 3, 26 – 45%; 4, 46 – 75%; and 5, 76 – 100% [30].

Western blot analysis

Mouse kidney tissues were added to RIPA lysate (C1053, Beijing Pulilai Gene Technology Co., Ltd), the supernatant was centrifuged, and the BCA protein quantification kit (E-BC-K318-M, Elabscience) was used to quantify the total proteins, and the proteins were separated by dodecyl sodium dodecylbenzene sulfonate gel electrophoresis (SDS-PAGE) (151 – 21 – 3, Xilong Scientific Co., Ltd) and then transferred to a PVDF membrane (IPVH00010, Millipore), which was closed, and then the membrane was incubated with rabbit anti-ASC (bs-6741R, Bioss, 1 : 500) and rabbit anti-NLRP3 (BF8029, Affinity, 1 : 500), the PVDF membrane was incubated with the secondary antibody at room temperature, the PVDF membrane was wetted with luminescent solution, and the membrane was placed in an ultra-high-sensitivity chemiluminescence imaging system (Chemi DocTM XRS+, Bio-Rad Laboratories) for development.

Enzyme-linked immunosorbent assay

The levels of IL-1β (MM-00040M1, Jiangsu Enzyme Immune Industrial Co., Ltd), IL-18 (MM-0169M1, Jiangsu Enzyme Immune Industrial Co., Ltd), and TNF-α (MM-0132M1, Jiangsu Enzyme Immune Industrial Co., Ltd) in the kidney tissues of mice were detected by ELISA. Take the homogenate of kidney tissue from mice and follow the instructions.

Statistical analysis

All data were statistically analyzed using GraphPad Prism 8 and IBM SPSS Statistics 26, comparisons between multiple groups were analyzed by ANOVA, and the LSD test was used for post hoc tests, with P < 0.05 indicating significant differences.

Declarations

Ethics approval and consent to participate

All procedures of the experiments were performed in accordance with ARRIVE guidelines (https://arriveguidelines.org). The study was approved by the Laboratory Animal Ethics Committee of Jiangxi Zhonghong Boyuan Biotechnology Co., Ltd, Jiangxi, China. Approval number: 2 022 081 902.

Availability of data and materials

The data that underlie and support the findings of this study can be made available by the corresponding author upon reasonable request.

Contributorsʼ Statement

Data collection: J. H. Z, M. Z. G, Q. C, T. C, D. D. R, M. W, F. M. H, L. C, Y. B. Z, J. W. L; design of the study: L. C, Y. B. Z, J. W. L; statistical analysis: J. H. Z, M. Z. G, Q. C, T. C, D. D. R, M. W, F. M. H; analysis and interpretation of the data: J. H. Z, M. Z. G, Q. C, T. C, D. D. R, M. W, F. M. H; drafting the manuscript: J. H. Z, T. C, L. C, Y. B. Z, J. W. L; critical revision of the manuscript: L. C, Y. B. Z, J. W. L, D. D. R, M. W, F. M. H, M. Z. G, Q. C.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Correspondence

Publication History

Received: 29 September 2024

Accepted after revision: 10 January 2025

Article published online:
24 January 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar

• Supplementary Material