Jing Lian, Yisheng Xu, Ji Shi, Pengpeng Liu, Yue Hua, Chao Zhang, Tianhang Ren, Guoming Su, Shizan Cheng, Zixuan Nie, Tianzhu Jia
Abstract
Acute kidney injury (AKI) is a sudden loss of renal function with a high mortality rate and inflammation is thought to be the underlying cause. The phenylpropanoid components acteoside (ACT) and isoacteoside (ISO), which were isolated from Cistanche deserticola Y.C.Ma, have been reported to have preventive effects against kidney disorders. This study aimed to investigate the anti-inflammatory properties and protective mechanisms of ACT and ISO. In this investigation, kidney function was assessed using a semi-automatic biochemical analyzer, histopathology was examined using Hematoxylin-Eosin staining and immunohistochemistry, and the concentration of inflammatory cytokines was assessed using an enzyme-linked immunosorbent assay (ELISA) test. In addition, using Western blot and q-PCR, the expression of proteins and genes connected to the NF-κB signaling pathway in mice with lipopolysaccharide (LPS)-induced AKI was found. The findings showed that under AKI intervention in LPS group, ACT group and ISO group, the expression of Rela (Rela gene is responsible for the expression of NFκB p65 protein) and Tlr4 mRNA was considerably elevated (P<0.01), which led to a significant improvement in the expression of MyD88, TLR4, Iκ-Bɑ and NF-κB p65 protein (P<0.001). The levels of Alb, Crea and BUN (P<0.001) increased along with the release of downstream inflammatory factors such as IL-1β, IL-6, Cys-C, SOD1 and TNF-α (P<0.001). More importantly, the study showed that ISO had a more favorable impact on LPS-induced AKI mice than ACT. In conclusion, by inhibiting NF-κB signaling pathway, ACT and ISO could relieve renal failure and inflammation in AKI, offering a fresh possibility for the therapeutic management of the condition.
Introduction
Acute kidney injury (AKI) is a severe clinical and multifactorial illness characterized by a sudden loss of renal functioning [1]. It is marked by impaired renal tubular reabsorption and decreased glomerular filtration rate [2]. Global statistics show that AKI-induced morbidity and mortality are rather high [3]. According to clinical data, approximately 35% of critical care patients suffer acute kidney failure [4,5]. Intensive care unit (ICU) patients with AKI have a death rate of 60–80% [6,7]. Furthermore, there is evidence that the death rate among individuals with AKI, particularly those requiring dialysis, could reach over 70 percent [8]. AKI patients also encounter a number of complications [9]. AKI is becoming more and more prevalent, and the elevated mortality rate and poor prognosis indicate that it poses a severe health concern [10]. Despite decades of research, the cause of AKI remains unidentified and effective therapies are in short supply. As a result, it is essential to discover novel and potent medications for the treatment of AKI. Animal models that accurately mirror human illnesses are extremely helpful. Gram-negative bacteria infection can now cause renal ischemia, or a deterioration in renal perfusion [11] as well as alterations to renal function [12]. Lipopolysaccharide (LPS) is a biological inducer that has been widely employed for building AKI model [13].
Materials and methods
1.1 Animals
A total of 60 specific pathogen Free (SPF) BALB/c mice (Male, 6–8 weeks old,18~22 g) were acquired from Liaoning Changsheng Biotechnology Co. (Production certificate: SCXK(LIAO) 2020–0001). All mice were housed at constant room temperature (25±2°C) and atrelative humidity levels of 60±10%. The circumstance was subjected to 12-hour cycles of darkness and light, and mice were provided unrestricted accessibility to food or water. Before beginning the experiments, the mice were given at least 7 days to get used to these environments.
Results
2.1 ACT and ISO ameliorate renal dysfunction in LPS-induced AKI mice
The mice in LPS group showed the symptoms of physical weakness, sluggish responsiveness, lethargy, dull and erect hair, listlessness, reduced urine volume, deepened urine color, no animal suffered hematuria, and several mice developed diarrhea. After receiving lipopolysaccharide, the activity of mice was significantly reduced. However, the DXMS, ACT, and ISO groups of animals had better circumstances as compared to LPS group. The serum concentrations of creatinine, blood urea nitrogen, albumin levels and kidney index were tested to evaluate kidney function [29]. As shown in Fig 2, when comparing the LPS group to the Con group, the kidney index (P < 0.01) and the levels of serum for Crea (P < 0.001), BUN (P < 0.001), and Alb (P < 0.001) all showed a substantial rise. While LPS-treated mice that received either ACT or ISO treatment had a distinct reduction in Crea, BUN, and Alb levels as well as kidney index (P< 0.05 or P< 0.01). Additionally, serum BUN (P < 0.05) and Alb (P < 0.05) levels were decreased more effectively by ISO than ACT.
Discussion
Acute kidney injury (AKI), also recognized as acute renal failure (ARF), is the abrupt collapse of renal function. AKI, as a systemic illness, is a cluster of syndromes that include urinary tract obstruction [31], sepsis [32], heart failure, cardiorenal syndrome [33], and hepatorenal syndrome, all of which have been shown to be associated with significant morbidity and mortality [34]. AKI has been reported in more than 50% of patients in intensive care and affects around 10–15% of hospitalized patients, and AKI rates in specialist hospital departments such as transplant centers, intensive care units, oncology, and cardiac surgery can reach 50% or higher [35]. AKI pathophysiology can range from a reduction in glomerular filtration rates (GFR) caused exclusively by local or systemic hemodynamic alterations caused by reversible tubular stress or injury to frank tubular necrosis, which results in an increase in serum Crea and BUN levels as well as proteinuria [36]. There is no pharmaceutical treatment for reversing renal damage that has been tried in clinical trials to yet. AKI cannot be avoided or treated with particular medications or therapies. Natural products have been demonstrated in several studies to be safe and effective, which can shorten the time and expense involved in developing new drugs.
Acknowledgments
We thank the editor-in-chief and reviewers for their helpful feedback that improved this article.
Citation: Lian J, Xu Y, Shi J, Liu P, Hua Y, Zhang C, et al. (2024) Acteoside and isoacteoside alleviate renal dysfunction and inflammation in lipopolysaccharide-induced acute kidney injuries through inhibition of NF-κB signaling pathway. PLoS ONE 19(5): e0303740. https://doi.org/10.1371/journal.pone.0303740
Editor: Partha Mukhopadhyay, National Institutes of Health, UNITED STATES
Received: July 7, 2023; Accepted: April 30, 2024; Published: May 15, 2024
Copyright: © 2024 Lian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting information files.
Funding: The experiment was supported by the National Natural Science Foundation of China (Grant No. 81874345), the Natural Science Foundation of Liaoning Province (Grant no.2020-MS-223). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There are no conflicts of interest to declare.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: ACT, Acteoside; AKI, Acute kidney injury; Alb, Albumin; BCA, Bicinchoninic acid; BUN, Blood urea nitrogen; Crea, Creatinine; Cys-C, Cystatin C; DXMS, Dexamethasone; EAE, Encephalomyelitis; ELISA, Enzyme-linked immunosorbent assay; FMF, Familial mediterranean fever; GFR, Glomerular filtration rates; IL-1β, Interleukin-1β; IL-6, Interleukin-6; ISO, Isoacteoside; LPS, Lipopolysaccharide; MyD88, Myeloid differentiation primary response gene 88; PBS, Phosphate buffered solution; PCR, Polymerase Chain Reaction; PVDF, PolyVinylideneFluoride; SOD1, Superoxide Dismutase1; TLR4, Toll-like receptor 4; TNF-α, Tumor necrosis factor α
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0303740#abstract0
