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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 5  |  Page : 937-945
Aspirin-Triggered Lipoxin Protects Lipopolysaccharide-Induced Acute Kidney Injury via the TLR4/MyD88/NF-κB Pathway

1 Department of Pediatrics, Jinling Hospital, Southern Medical University, Nanjing, Jiangsu, China
2 Department of Pediatrics, BenQ Medical Center, Nanjing Medical University, Nanjing, Jiangsu, China

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Date of Web Publication21-Nov-2020


The protective effect of aspirin-triggered lipoxin (ATL) on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and its possible mechanisms were explored. To induce acute renal injury, mice were treated with LPS. Concentration of serum creatinine (SCr) and blood urea nitrogen (BUN) was detected, and inflammatory cytokines and AKI biomarkers were determined by ELISA. The relative protein expression levels of TLR4/myeloid differentiation factor 88 (MyD88)/NF-κB signal pathway was assessed by Western blot. Mice subjected to LPS (4 mg/kg) treatment exhibited AKI demonstrated by markedly increased SCr and BUN levels compared with controls (P <0.01). Treatment with ATL decreased SCr and BUN levels after LPS injection (P <0.01). AKI biomarkers, such as urine NGAL, KIM-1, netrin-1, and L-FABP levels, increased by LPS and were inhibited by ATL (P <0.01). ATL also reduced LPS-induced secretion of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, and IL-8 (P <0.01). Furthermore, mice pretreated with ATL before exposure to LPS showed a reduction in TLR, MyD88, and p65 phosphorylation (P <0.01), which are the key factors of the TLR/MyD88/NF-κB signaling pathway. These results indicated that ATL had protective effects on renal function and showed amelioration of LPS-induced kidney injury. The mechanisms underlying the protective effects of ATL can be considered are related to attenuation of the TLR4/MyD88/NF-κB signaling pathway.

How to cite this article:
Zhang P, Peng H, Gao C, Fan Z, Xia Z. Aspirin-Triggered Lipoxin Protects Lipopolysaccharide-Induced Acute Kidney Injury via the TLR4/MyD88/NF-κB Pathway. Saudi J Kidney Dis Transpl 2020;31:937-45

How to cite this URL:
Zhang P, Peng H, Gao C, Fan Z, Xia Z. Aspirin-Triggered Lipoxin Protects Lipopolysaccharide-Induced Acute Kidney Injury via the TLR4/MyD88/NF-κB Pathway. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2023 Feb 9];31:937-45. Available from: https://www.sjkdt.org/text.asp?2020/31/5/937/301200

   Introduction Top

Acute kidney injury (AKI) is a common complication, occurring in approximately 35% of intensive care unit (ICU) admissions and 5% of hospitalizations.[1],[2] AKI considerably increases morbidity, mortality, and significant health-care and economic burden, independent of other comorbidities.[3] A meta-analysis of observational studies demonstrated that survivors of AKI had a long-term mortality rate of more than twice that of patients without AKI.[4] AKI survivors exhibit a significant risk of developing chronic morbidities, such as chronic kidney disease and end-stage renal disease. Recent studies showed that the pathogensis of AKI includes ischemia reperfusion injury, sepsis, inflammatory, drug toxicity, thrombosis, endothelial cell damage, and autophagy. Among those, sepsis and septic shock are the major causes of AKI in the critical illness. Septic AKI has become an important medical issue confronted by clinical practitioners,[5] and the most common cause of AKI in hospitalized patients is sepsis.[6] A multi-center, large-sample, epidemiological study showed that septic AKI was the most common cause of death in Chinese pediatric patients, accounting for 34.9%.[7]

Lipoxin (LX) is an eicosanoid that is endogenously produced through lipoxygenase action. It was discovered in 1984 through interaction(s) between the 5- and 15-lipoxygenase pathways in human leukocytes.[8] LX was previously considered an antiinflammatory lipid mediator. The production of LX is enhanced by aspirin through acetylation of cyclooxygenase-2, via a mechanism known as aspirin-triggered lipoxin (ATL), which shares the potent antiinflammatory actions of LX but is more resistant to metabolic inactivation.[9] However, ATL has a long-lasting biologic activity and constitutes a better therapeutic option. ATL can reduce the excretion of proinflammatory cytokines, block inflammatory cell recruitment, and decrease vascular permeability. ATL leads to the resolution of inflammation through its immune and angiogenic modulatory properties. In endothelial cells, ATL can block the generation of reactive oxygen species.[10],[11] In immune cells, ATL can inhibit leukocyte–endothelial interaction, tumor necrosis factor-alpha (TNF-α) secretion, and nuclear factor kappa B activation.[12]

Lipopolysaccharide (LPS), which is the major constituent of the outer membrane of Gram-negative bacteria, elicits strong immune and inflammatory responses in animals. LPS can induce early clinical manifestations of sepsis including AKI, which has been widely used in establishing a sepsis animal model for its simplicity.[13] Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs), such as LPS, are germlineencoded pattern recognition receptors that are most well known in the innate immune response and are responsible for the inflammatory cascade in sepsis. TLRs are expressed in various cell types, including dendritic cells (DCs), B cells, and kidney tubular epithelial cells.[14] TLR2 is particularly involved in signal transduction of cellular responses to lipoproteins/lipopeptides, Gram-positive bacteria, and mycobacterial wall constituents. Signal transduction through TLRs is partially mediated by a TLR adapter protein myeloid differentiation factor 88 (MyD88). MyD88 is widely used by all TLRs except TLR3 and activates the mitogen-activated protein kinases (MAPKs) and the translocation of nuclear factor-κB (NF-κB) from cytosol to the nucleus to induce various inflammatory cytokines, for example, interleukin (IL)- 1β (IL-1β), IL-6 and TNF-α.[15] In addition, LPS activates NF-κB through TLR4 and MyD88 in endothelial cells.[16] Therefore, TLR4/MyD88/NF-κB signaling is an important mediator of AKI development. Several studies have shown the importance of TLRs in the development of sepsis, but few studies have correlated the activation of TLRs with the development of AKI. Therefore, the aim of this study was to investigate whether ATL could protect renal function and improve animal survival by inhibiting the TLR4/ MyD88/NF-κB signaling pathway during the early phase of AKI induced by LPS, to provide potential insights of therapeutic targets to septic AKI.

   Materials and Methods Top


Animal-handling procedures were conducted in accordance with the Laboratory Animal Regulations of the Scientific Bureau of Jiangsu Province, China.

Experimental procedures[17] were performed in 10–14-week-old male C57BL/6J wild-type mice obtained from the department of Comparative Medical Science, Jinling Hospital. The animals were maintained at a 12 h:12 h light/dark cycle in air-conditioned rooms at 22°C ± 2°C.

Acute kidney injury mouse model

All the mice were randomly divided into five groups (8 per group) as follows: the control group, LPS 6 h group, LPS 12 h group, ATL plus LPS 6 h group, and ATL plus LPS 12 h group. Control group mice were given intra-peritoneal injection of 1.6 mL/kg NS at experimental start time “0” and mice from the LPS groups and ATL plus LPS groups were given an intraperitoneal injection of LPS 10 mg/kg at experimental start time “0,” before LPS intraperitoneal injection. In addition, mice from the ATL plus LPS groups were given an intraperitoneal injection of ATL 5 μg at experi-mental start time “2 h”. At 2 h after LPS injection, the physical activities of some mice decreased slightly but no mice showed weight loss, poor body, or abnormal skin during the treatment. All the mice were given an intra-peritoneal injection of 10% chloral hydrate 3.5 mL/kg for anesthesia, then a ventral midline longitudinal incision and separation of the urinary bladder was performed to facilitate bladder puncture and urine collection. Then, the chest of each mouse was dissected and blood was collected from the heart (the LPS 6 h group and ATL plus LPS 6 h group at time “6 h,” the control group and ATL plus LPS 12 h group at the time “12 h”).

LPS from Escherichia coli

055:B5 was obtained from Sigma-Aldrich Chemical Co, Se Louis (USA). ATL was obtained from Cayman Chemical Co. Hamburgh, (GER). Mouse TNF-α, IL-1β, IL-6, and IL-8 ELISA kits were purchased from Nanjing Jiancheng Bioengineering Institute (CN).

Measurement of urine and blood

Urine and blood samples were centrifuged (2000 rpm, 15 min) and preserved at −70°C. Serum Cr and blood urea nitrogen (BUN) concentrations were measured by the Clinical Laboratory of Jingling Hospital (Nanjing, China) via an automatic biochemistry analyzer (Beckman Coulter LX20, Beckman, USA). Urine NGAL, KIM-1, netrin-1, L-FABP and serum TNF-α, IL-1β, IL-6, and IL-8 were measured by ELISA kits (Nanjing Jiancheng Bioengineering Institute, Nanjing, China) according to the manufacturer's instructions. The right kidney was placed in 4% paraformaldehyde/phosphate-buffered saline and subsequently embedded in paraffin, and the left kidney was snap frozen in liquid nitrogen and stored at −80°C.

Measurement of renal parameters

Mouse kidneys were homogenized in buffer supplemented with protease inhibitors. Samples with equal amounts of total protein (50 mg/mL) were processed for Western blotting by using antibodies against TLR4, MyD88, phosphorylated-IκB, phosphorylated-p65, and phosphorylated-p52 and cleaved with diluting ratio varying from 1:2000 to 1:5000.

   Statistical Analysis Top

All data were expressed as mean and standard error of means. Comparisons among groups were conducted with one-way ANOVA and subsequent Student's t-test. The level of significance was set at P <0.05 in all cases.

   Results Top

Effects of aspirin-triggered lipoxin on lipopolysaccharide-induced dysfunction of kidney function of acute kidney injury

As important indexes, BUN and SCr were used for the assessment of renal function. As shown in [Figure 1], LPS upregulated the levels BUN and SCr in mice, which indicated successful establishment of AKI. The maximum values of BUN and SCr appear at 6 h and 12 h after LPS injection, respectively. However, treatment of AKI mice with ATL reduced the levels of BUN and SCr. In samples taken at 6th h from ALT+LPS groups, the BUN level decreased to the lowest point. However, the levels of SCr gradually decreased as time passed.
Figure 1: Levels of blood urea nitrogen (a) and serum creatinine (b) assessed using biochemical analysis. Data are represented as mean ± standard deviation of eight animals of each group.
*P <0.01, compared to control group; #P <0.01 compared to lipopolysaccharide group.

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Effects of aspirin-triggered lipoxin on Lipopolysaccharide-induced kidney damage

To investigate the protective effects of ATL, urine NGAL, KIM-1, Netrin-1, and L-FABP levels were detected by ELISA. As shown in [Figure 2], LPS upregulated the urine NGAL, KIM-1, Netrin-1, and L-FABP levels in AKI mice. However, AKI mice treated with ATL significantly abrogated the abovementioned changes induced by LPS. Treatment with ATL significantly reduced the urine levels of NGAL, KIM-1, Netrin-1, and L-FABP. With the progression of ATL treatment, the levels of AKI biomarkers gradually stabilized. It was revealed that ATL could alleviate renal injury induced by LPS.
Figure 2: Levels of NGAL (a), KIM-1 (b), Netrin-1 (c), and L-FABP (d) in urine were measured by ELISA. Data are represented as mean ± standard deviation of eight animals of each group.
*P <0.01, compared to control group; #P <0.01 and ##P <0.05 compared to lipopolysaccharide group.

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Effects of aspirin-triggered lipoxin on lipopolysaccharide-induced inflammatory responses

Inflammatory response was an important factor in the progression of acute renal injury, so we analyzed the levels of inflammatory cytokines within the groups. As shown in [Figure 3], the inflammatory cytokines (IL-1β, IL-8, IL-6, and TNF-α) were induced by LPS, the levels of which were significantly increased at 6 h after LPS injection. All the cytokines except IL-8 reached the maximum value at 6 h after LPS injection, and the peak time of IL-8 was 12 h. These data suggested that ATL had attenuated LPS-induced inflammatory responses by inhibiting the secretion of inflammatory cytokines successfully.
Figure 3: Levels of interleukin-1β (a), interleukin-8 (b), interleukin-6, (c) and tumor necrosis factor-alpha (d) in serum was performed by ELISA. Data are represented as mean ± standard deviation of eight animals of each group.
*P <0.01, compared to control group; #P <0.01 and ##P <0.05 compared to lipopolysaccharide group.

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Effect of aspirin-triggered lipoxin on the TLR4/MyD88/NF-κB signal pathway

TLR/MyD88 plays an important role in LPS-induced AKI. To investigate the anti-inflammatory mechanism of ATL, we assessed the expression of TLR4, MyD88, and the related proteins expression in the NF-κB signal pathway. As shown in [Figure 4], the expression of TLR4 and MyD88 assessed by Western blot analysis in the kidneys significantly increased in mice injected with LPS compared with those in the normal controls, and they displayed a time-dependent relationship. However, these elevated expression levels of TLR4 and MyD88 in the kidneys induced by LPS were suppressed by ATL treatment.
Figure 4: Expression of TLR4 and myeloid differentiation factor 88 in kidney tissue performed by western blot. Data are represented as mean ± standard deviation of 8 animals of each group.
*P <0.01, compared to control group; #P <0.01 and ##P <0.05 compared to lipopolysaccharide group.

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Furthermore, we also examined the expression of proteins related to the NF-κB signal pathway. As shown in [Figure 5]a, ATL almost completely blocked the LPS-induced accumulation of IκB phosphorylation, and the effect was more obvious with time. As shown in [Figure 5]a and [Figure 5]b, the kidney tissue proteins p65 and p52 and phosphorylation of p65 and p52 expression were tested by Western blot. LPS significantly induced the expression of p65 and p52, both in the LPS 6 h and 12 h groups. ATL downregulated the protein expression levels of p65 and p52, both of which were lower in LPS+ATL groups than that in LPS groups. LPS caused p65 phosphorylation, but p52 phosphorylation in all the groups was not different. These results suggested that ATL may reduce TLR4/MyD88/NF-κB signaling pathway activation by regulating phosphorylation of p65.
Figure 5: Expression of IκB and p65 and p52 phosphorylation in kidney tissue performed by Western blot. Data are represented as mean ± standard deviation of eight animals of each group.
*P <0.01, compared to control group; #P <0.01 compared to LPS group.

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   Discussion Top

AKI frequently occurs in patients with severe sepsis and septic shock,[18] with sepsis being regarded as the most common cause of AKI in ICUs.[19] The pathogenesis of sepsis-associated AKI is believed to be an interplay of systemic and renal inflammation, hypoxia, and dysregulated renal bioenergetics. There are no pharmacological interventions approved for the treatment of AKI except renal replacement therapy. Therefore, there is an urgent medical need to investigate novel pharmacological interventions to prevent or treat AKI.

A variety of animal models have been established to investigate the specific molecular events occurring in AKI. The most frequently employed model is the LPS-induced AKI, which can produce consistent renal tissue damage, and the model is similar to that observed in humans.[20],[21] We had established a mouse AKI model by treating BALB/c mice with a single intraperitoneal injection of 10 mg/kg of LPS. LPS significantly upregulates the production of SCr and BUN. However, after treatment with ATL, the levels of SCr and BUN were lower. Our present study showed that ATL improved the kidney functions of mice induced by LPS, revealing the therapeutic role of ATL in LPS-induced AKI.

Biomarkers have recently been intensively investigated and have been shown to be potentially suitable for risk stratification and early diagnosis of AKI, prediction progression, severity and outcomes of AKI.[22] In the present experiment, urine NGAL, KIM-1, netrin-1, and L-FAPB had significantly increased in LPS groups compared with the control group. However, in the ATL+LPS groups, the expression of biomarkers was obviously inhibited by ATL. All the expression levels of biomarkers had evidently increased at 6 h after LPS injection, and there was no significant difference compared with the LPS 12 h groups. Similarly, we also observed that the upregulated BUN and SCr with LPS was intervened and downregulated after ATL treatment, which indicated that NGAL, KIM-1, netrin-1, and L-FAPB are useful early AKI biomarkers, and that ATL could remedy AKI, alleviate tubular damage, and play a renal protective role. In the model groups, the level of TNF-α, IL-1β, IL-6, and IL-8 as an index of pro-inflammatory mediators is also higher. ATL as a pharmacological treatment had reduced the release of those factors. It is indicated that the protection of ATL against AKI occurs by regulating AKI biomarkers and inflammatory cytokines.

TLRs play important roles in innate immunity against all types of pathogens by recognizing various pathogen-associated molecular patterns. TLR2 and TLR4 are the best-characterized members in the TLR family. TLR2 is involved in the recognition of a wide range of bacterial products, such as lipoprotein, fatty acids, zymosan, and peptidoglycan, whereas TLR4 is activated by LPS and heat-shock proteins (HSP). TLRs, especially MyD88, are involved in renal injury; TLR2 and TLR4 are constitutively expressed predominantly in the renal epithelial cells of proximal and distal tubules, as well as the epithelium of glomerular and endothelial cells.[23] Therefore, in this study, we investigated the role of TLR4 and MyD88 in the treatment of ATL in LPS-induced AKI. Our study showed that LPS could increase TLR4 and MyD88 protein levels, which both of them overexpressed from the time 6 h after LPS injection, and reaching their highest levels at 12 h. ATL successfully inhibited the expression of TLR4 and MyD88, as well as TNF-α, IL-1β, IL-6, and IL-8, the inflammatory cytokines, which were closely related with TLR4/MyD88 activation.

The NF-κB pathway has been subdivided into classical and alternative NF-κB pathways. In the classical pathway, NF-κB is primarily activated via IκB kinase-mediated phosphorylation and ubiquitinated. In this study, a significant increase in IκB phosphorylation levels was seen in the kidney of mice 6 h after injection with LPS, and these values increased with time. Still, in mice pretreated with ATL, after injection with LPS, IκB phosphorylation levels were lower than that in the LPS groups. Phosphorylation of p65 is an important step in the classic NF-κB pathway, after which, NF-κB is transported to the nucleus where it is able to transactivate different target genes. Phosphorylation of IKKα is involved in the noncanonical NF-κB pathway, which activates Rel B/p52 heterodimers. We examined p65 phosphorylation and p52 phosphorylation under the effects of LPS stimulation and ATL treatment to determine whether the canonical pathway or noncanonical pathway or both are involved in AKI induced by LPS. In this study, we found that LPS caused the phosphorylation of p65, however no significant differences in p52 phosphorylation were seen between all groups, suggesting that LPS induced the classical NF-κB pathway but did not activate the alternative route of NF-κB pathway activation by participating in inflammation. This result is consistent with the former data.[24]

LX has been confirmed as an anti-inflammatory factor attenuating acute lung injury, acute liver injury, and acute myocardial injury,[25],[26],[27],[28] however research on the protective function of ATL on AKI has not been reported. Our study showed that ATL could reduce the excretion of pro-inflammatory cytokines and modulate excessive neutrophil stimulation and factors. We confirmed that ATL performed significant effects on NF-κB activation, similar to previous research.[12] The levels of p65 and p52 were downregulated by ATL, which also inhibited phosphorylation of p65 in both ATL+LPS 6 h and 12 h groups. NF-κB-associated protein expression levels were lower than in the LPS 6 h and 12 h groups. All the results support the notion that ATL is involved in modulation of LPS-induced inflammatory responses via the TLR4/MyD88/NF-κB signal pathway. However, our article only discusses the animal experiments, so in vitro experiments are the target of our future research.

In conclusion, the present study identified that, NGAL, KIM-1, netrin-1, and L-FAPB were changed significantly by LPS. LPS-induced AKI is mediated by the upregulation of the TLR4/MyD88/NF-κB pathway, and treatment of ATL attenuated LPS-induced AKI in mice has a significant renoprotective effect on the development and progression of septic AKI.

Conflict of interest: None declared.

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Correspondence Address:
Zhengkun Xia
Department of Pediatrics, Jinling Hospital, Southern Medical University, Nanjing, Jiangsu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.301200

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