The protective effect of CD200 on hemorrhage/sepsis-associated acute kidney injury

doi:10.21203/rs.3.rs-2469358/v1

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The protective effect of CD200 on hemorrhage/sepsis-associated acute kidney injury

https://doi.org/10.21203/rs.3.rs-2469358/v1

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Background Acute kidney injury is a serious complication of morbidity and mortality with critically ill patients in short and long-term. Severe trauma patients especially followed infection will induce acute kidney injury.

Methods C57BL and C57BL background CD200 deficiency mice were applied to undergoing the operation of cecal ligation and puncture following hemorrhage. The model was used to simulate the process of shock patients followed infection, which associated with acute kidney injury clinically. Blood and kidney tissues were harvested 24 h after hemorrhage/cecal ligation and puncture. CD200 expression on neutrophils and monocytes in blood was stained and measured via flow cytometry analysis. Serum creatinine and blood urea nitrogen were measured according to the manufacturer’s instruction. Cytokines and counterpart RNA expression were detected via ELISA and RT-PCR, respectively. The severity of kidney injury was assessed by pathologists. The protein level of neutrophil gelatinase-associated lipocalin and high mobility group 1 was measured via western blot.

Outcome CD200 expression was elevated on neutrophils and monocytes in blood. Furthermore, the severity of kidney injury of histology, assessed by pathologists, was much aggravated on acute kidney injury and even exacerbated on CD200 deficiency mice. The levels of serum creatinine and blood urea nitrogen were all increased in CD200 deficiency mice. Cytokines of IL-6 and TNF-α increased in acute kidney injury and even aggravated in CD200 deficiency mice, but IL-10 was demonstrated the reversed trend. The consistent trend of RNA expression of cytokines including IL-6, TNF-α and IL-10 was corroborated via RT-PCR. As western blot demonstrated, the protein level of neutrophil gelatinase-associated lipocalin was increased and high mobility group 1 decreased in CD200 deficiency mice.

Conclusion CD200 may be involved in the development of hemorrhage/cecal ligation and puncture associated acute kidney injury. It may be speculated that CD200 plays a protective effect in acute kidney injury potentially through inhibiting neutrophil gelatinase-associated lipocalin and activating high mobility group 1 signaling pathway.

Biological sciences/Immunology

Earth and environmental sciences/Biogeochemistry

Health sciences/Biomarkers

Health sciences/Diseases

Health sciences/Medical research

Acute kidney injury (AKI) is still a common complication of a serious condition that affects millions of patients worldwide. Under the consensus criteria for definition and classification[1], significant management with multiple clinical treatments[2], the incidence, severity and outcome of AKI remain obscured[3]. AKI has been a major public health problem that leads to decreased survival and increased progression of underlying chronic kidney disease.

It has been reported that CD200 was expressed on kidney glomeruli[4]as an independent immune modulator agent[5]. However, little is known about the role of CD200 on the regulation of inflammation transmitted from the periphery[6]. Here, we proposed that peripheral neutrophils and monocytes play key roles during the periphery-kidney connection. Furthermore, we demonstrated that CD200 signaling is crucial in regulating AKI.

The present work has been reported in accordance with the ARRIVE (Animals in Research; Reporting In Vivo Experiments)[7]. All experiments were performed in accordance with the guidelines of the Institutional Animal Ethics Committee of our affiliation.

Animals

Wild type C57BL control male mice (aged 8-12 weeks; 25-30 g) were obtained from the Animal Experimentation Center. C57BL background CD200 gene deficient (CD200^−/−) mice were designed from Shanghai Model Organisms Co. Ltd (Shanghai, China). Wild type mice were randomized to either hemorrhage (Hem)/cecal ligation and puncture (CLP) or sham Hem/CLP group. In summary, mice were marked with sequence number and allocated into control or experimental groups. As we had found, there were not any differences of CD200 expression on neutrophils and monocytes, and kidney injury under optical microscope. C57BL background CD200 gene deficient mice were allocated into the Hem/CLP group only. Mice were housed under specific pathogen-free conditions and provided standard laboratory chow and water freely one week before experiment.

Experimental design

The mouse model of AKI was conducted via hemorrhagic shock followed by the induction of CLP to simulate patients with hypovolemia shock followed secondary infection. We used a 90-min and fixed pressure (35 ± 5 mmHg) Hem at the atmosphere of isoflurane, followed by resuscitation with Ringers lactate injection at 4 times drawn blood volume via micro-injection pump. After resuscitation, mice were taken into animal room with standard laboratory chow and water freely. The second challenge of sepsis was inducted via CLP at 24 h post Hem. While the sham Hem/CLP group was done without hypovolemia and cecal ligation and puncture, just exposed and ligated the arterial femoralis as Hem and exposed the enterocoelia as CLP.

Mice were anesthetized at 24 h post Hem/CLP by isoflurane, and sacrificed blood was collected via cardiac puncture using heparinized syringes. Blood was centrifuged, and plasma sample was separated after centrifugation at 3000g for 5 min. The concentrations of IL-6, TNF-α, and IL-10 in plasma were detected using enzyme-linked immunosorbent assay (ELISA) kits according to manufacturer’s instructions (R&D system, USA). To affirm the reproductive results, all experiments were repeated twice.

Flow cytometry analysis

Blood was harvested 24 h post Hem/CLP and single cell suspensions were stained with fluorescence labeled antibody. Antibody information as following: anti-CD11b(APC, code: 17-0041-82; clone: GK-1.5, eBioscience USA); anti-F4/80 (Brilliant violet, code:123131; clone: BM8, Biolegend USA); anti-Ly6G(Vio-Blue, code: 11-0081-85; clone: 53-6.7, eBioscience USA); CD200 (PE, code: 11-0081-85; clone: 53-6.7, eBioscience USA).

Cytokines expression in kidney

Kidneys were harvested 24 h post Hem/CLP and dissolved into protein solution via lysis buffer. Protein level was set at 250μg/ml. Enzyme-linked immunosorbent assay (ELISA) was conducted following manufacture’s introduction. Immune 96 well ELISA plates were used for coating, blocking, detecting and read at subtract 550 nm values from 450 nm values to correct for optical imperfections in the microplate. Use curve-fitting statistical software to plot a four-parameter logistic curve fit to the standards and then calculate results for the test samples.

Histopathology assay

Kidney tissues were harvested 24 h post Hem/CLP. Kidney samples were fixed in 10% buffered paraformaldehyde for at least 24 h. Sections (4-5 μm) on slides were deparaffinized in xylene, rehydrated in decreasing concentrations of ethanol, and stained with hematoxylin and eosin (H&E). All sections were graded blindly by three pathologists under light with the following score scale:0, none; 1, individual cell necrosis; 2, ≤30% lobular necrosis; 3, ≤60% lobular necrosis; 4, >60% lobular necrosis[8].

Assessment of blood urea nitrogen and serum creatinine

Levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were measured by automatic dry biochemical analyzer (Hitachi Auto Analyzer 7170, Japan). The levels of BUN and Scr were examined by automatic biochemical analyzer (TC6010 L, Tecom Science Corporation, Jiangxi, China).

RNA isolation and real-time PCR analysis

Total RNA was isolated from the homogenate of the kidney with Trizol reagent (Invitrogen). Cellular RNA was treated with DNase I and then primed with a dT oligonucleotide and reversed transcribed with Superscript II. For real-time assays, PCR reactions were prepared in SYBR Green PCR Master Mix. DNA targets were amplified and analyzed with a Chromo Real-Time PCR Detection System (Bio-Rad Life Sciences). The murine primer sequences are shown as follows: Mouse GAPDH forward sequence:5-CCCCCAATGTGTCCGTCG-3, Reverse sequence: 5- CGGCATCGAAGGTGGAAGA-3; IL-6 forward sequence: 5-GGAGCCCACCAAGAACGAT-3, reverse sequence: 5-TCACCAGCATCAGTCCCAAGA-3; TNF-α forward sequence:5- TCTTCTCATTCCTGCTTGTGG-3, reverse sequence: 5- TTGGTGGTTTGCTACGACG-3.Total RNA was treated with DNase I to eliminate genomic DNA contamination, followed by synthesis of the first-strand using reverse transcription system. Reverse transcription was carried out and GAPDH was used as an internal control as prior study conducted [9]. The relative amount of mRNA was determined using the ΔΔCT technique as described previously[10]. The levels of mRNA were expressed as fold-changes after normalization to GAPDH.

Western-blotting analysis of neutrophil gelatinase-associated lipocalin and high mobility group 1

Kidneys were carefully excised and homogenized into lysis buffer (Termo, USA) to yield a homogenate. After centrifugation (12000 g for 10 min) at 4°C, protein concentration was detected by Bradford protein assay kit (Termo, USA) with bovine serum albumin as standard. Equal amounts of protein extracts separated discontinuously by 10% polyacrylamide gels (Life Technologies, Carlsbad, CA, USA) and transferred to nitrocellulose membranes (Life Technologies). After blockade of nonspecific binding sites, the membranes were incubated with various antibodies against neutrophil gelatinase-associated lipocalin (NGAL) or high mobility group 1 (HMGB1) (Cell Signal Technology, Danvers, MA, USA) for 2h at room temperature. Membranes were developed by chemiluminescence using an Amersham prime ECL Plus detection system (ChemiDoc 600 Imager, Ultra-Violet Product Ltd, UK). Signals were discontinuously assessed and normalized to the GAPDH signals (Image J, NIH).

Statistical analysis

SPSS 19.0 software was used for statistical analysis. The data are expressed as the mean ± standard error of the mean (SEM). Student’s unpaired t-test was used for comparisons between two means. For comparison of multiple ranges, we first measure the homogeneity of variance. When the homogeneity of variance was equal, one-way ANOVA followed by least significant difference (LSD) post homogeneity test was used. When the assumption of homogeneity of variances is not met, Welch’s test was applied and Dunnett T test was used for comparison of pairwise significance. Statistical significance was set at p < 0.05.

CD200 expression increased on neutrophils and monocytes

Neutrophils were stained with CD11b⁺Ly6G⁺ and monocytes with CD11b⁺F4/80⁺ in the present study. As the results demonstrated, the expression of CD200 on neutrophils (95%CI 4.82 - 51.71, p=0.025, Fig. 1A) in Hem/CLP group was increased significantly comparing with sham group, while the expression on monocytes also aggravated (95% CI 31.57 - 69.59, p<0.001, Fig.1B) in the study group.

The levels of Scr and BUN were all elevated in AKI

As results indicated, Scr increased significantly in AKI (95% CI 43.35 -85.88, p<0.001, Fig. 2A) comparing with control group, in addition, it was elevated in CD200 deficiency mice (95% CI 6.85 -44.88, p<0.001, Fig. 2A) compared with wild type. Another factor which indicates the severity of kidney, BUN, was assessed and increased in AKI (95% CI 3.14 -31.93, p=0.021, Fig.2B) comparing with control group, which also magnified in CD200 deficiency mice (95% CI 16.56-42.3, p<0.001, Fig.2B) compared with wild type.

The severity of kidney in CD200 deficiency mice was exacerbated

Three pathologists were invited to assess the severity of kidney histology following the criterion as stated. As the histologic sections demonstrated, renal tubules karyopyknosis, apoptosis, edema, and degeneration. We analyzed severity scores and found it increased significantly (95% CI 0.87 - 2.80, p=0.001, Fig.3) in AKI group comparing with control group. Furthermore, pathologists even found necrosis in CD200 deficiency mice. Notably, it was much deteriorated in CD200 deficiency mice (95% CI 0.08 – 2.25, p=0.037, Fig.3) compared with wild type.

Kidney was infiltrated with cytokines, which may deteriorate the injury

Cytokines of IL-6 (95% CI 2.43 – 44.72, p=0.032, Fig. 4A), TNF-α (95% CI 4.38 – 30.68, p=0.014, Fig. 4B) were elevated and IL-10 (95% CI -82.28 to -9.92, p=0.018, Fig. 4C) decreased in AKI comparing with control group. While in CD200 deficiency group, IL-6 (95% CI 12.61 – 67.74, p=0.006, Fig. 4A), TNF-α (95% CI 5.06 – 81.36, p=0.029, Fig. 4B) were also increased and IL-10 (95% CI -83.84 to -11.84, p=0.014, Fig. 4C) decreased compared with wild type as ELISA revealed. Gene expression was the key factor for protein levels. We detect the gene expression in the kidney to further confirm the infiltrated cytokines in kidney. As the RT-PCR demonstrated IL-6 (95% CI 7.82 – 47.68, p=0.016, Fig. 5A), TNF-α (95% CI 5.14 – 104.67, p=0.038, Fig. 5B) and IL-10 (95% CI 21.27 – 84.87, p=0.009, Fig. 5C) all increased in AKI in accordance with counterpart protein levels, except IL-10. In the CD200 deficiency mice, IL-6 (95% CI 16.82 – 112.23, p=0.015, Fig. 5A), and TNF-α (95% CI 7.85 – 99.06, p=0.029, Fig. 5B) increased significantly in AKI comparing with control group and IL-10 (95% CI -70.35 to -9.38, p=0.017, Fig. 5C) decreased compared with wild type.

Protein expression of NGAL and HMGB1

Previous studies had demonstrated urinary NGAL as a predictor of AKI[11], HMGB1 was increased in AKI serum[12, 13].Whether they were involved to modulate the process of AKI has not been revealed. We purified the protein from the kidney and detected them via western blot. As the results demonstrated, NGAL increased significantly in AKI (95% CI 49.90 – 171.00, p=0.006, Fig 6) comparing with control group and decreased in CD200 deficiency mice (95% CI -122.70 to -9.18, p=0.027, Fig 6) compared with wild type. While HMGB1 was augmented in AKI (95% CI 21.07 – 46.15, p=0.001) comparing with control group and even aggravated in CD200 deficiency mice (95% CI 7.47 – 72.20, p=0.022, Fig. 7) compared with wild type.

Despite previous research and current efforts, the pathogenesis of Hem/sepsis-associated AKI remains obscure. For the most part, the unbalance inflammation response plays a key role in the pathophysiology of Hem/sepsis associated AKI. The development of anti-inﬂammatory agents represents a promising research orientation[8]. In the current study, we demonstrated the protective effects of CD200 molecule on Hem/sepsis-associated AKI and provided new evidence regarding the potential effects on AKI.

AKI results from a variety of pathogenic stimuli, including ischemic and toxic insults, many of these insults converge to a common cascade of injury[14, 15]. While in the present study, we conducted hemorrhage and CLP to simulate ischemic and toxic/sepsis insults, which induced AKI completely. During the process of hemorrhage, which induced tubular cell death and initiated an innate immune response. Furthermore, CLP induced systemic infection increased immune loading. Necrotic cells released intracellular molecules, which activated identical pattern recognition receptors[16], causing them to secrete proinflammatory cytokines[17, 18]. These responses further guided various types of inflammatory cells to enter the site of cell death, which leaded to additional cell death, forming a vicious cycle of cell death inflammation[19, 20].

On the other hand, local immune cells, including macrophages, can also exhibit anti-inflammatory phenotypes, offset the effect of aberrant inflammation, and support the intrinsic repair of kidney[21]. Macrophages are polarized into a pro-inflammatory phenotype, which produces cytokines including TNF-α and IL-6, whereas in the repair phase, they become anti-inflammatory phenotypes, which offset the effect of aberrant inflammation and support tubular regeneration[22, 23]. We found kidney was infiltrated with immune cells including macrophages with high expression of CD200, which may verify CD200 was involved in the process of AKI development.

In the acute phase of AKI, macrophages rapidly accumulate in the kidney and drive disease progression by promoting inflammation and provoking local tissue injury[24, 25], whereas, in the later phase, they remove pro-inflammatory cell debris and enforce the resolution of inflammation as well as tissue regeneration in other cells without causing local damage[26, 27]. While CD200 was a co-inhibitory molecule and several studies also had confirmed the importance of CD200 signaling as a crucial down-regulator of inflammation[28, 29]. We also found CD200 was expressed on monocytes and increased significantly in AKI, which revealed the association with the progression of AKI.

We found CD200 suppressed the secretion of pro-inflammatory cytokines, TNF-α and IL-6, in addition, it enhanced the secretion of anti-inflammatory cytokine, IL-10, in CD200 deficiency mice. Moreover, Singh et al. [30] also found the consistency association of CD200 with cytokines in patients. This novel finding suggested that it may play an integral role in the pathogenesis of AKI via altering the regulation of inflammatory response. Although we found the gene of IL-10 expression increased but protein level decreased comparing with sham group, it may be explained that the gene expressed earlier than protein.

In addition, the histology revealed aggravated in CD200 deficiency mice and the injury score was significantly elevated as the pathologist assessed. BUN and Scr are important indicators of renal function in AKI[31]. Notably, CD200 deficiency mice revealed severe renal dysfunction demonstrated by increased levels of BUN and Scr. Though Scr is an imperfect measurement of dynamic glomerular filtration rate[32]. Consequently, novel biomarkers for earlier and more accurate detection of AKI are under investigation, but to date, these have not progressed to use in routine medical practice[33, 34]. Therefore, Scr remains the routinely used laboratory test for the diagnosis of AKI[35-38].

NGAL is widely expressed in kidney cells[39], and it had been reported that NGAL reduced apoptosis and increased proliferation in kidney through immune modulation and inflammation[40].NGAL gene was rapidly up-regulated and a prognostic marker in AKI[41, 42], which indicated NGAL is involved in the pathogenesis of AKI. Proteomic analysis verified that NGAL protein was induced in the kidney following Hem/sepsis-associated AKI, especially in CD200 deficiency mice in the present study, suggested that CD200 may modulate the progress of AKI via reducing the signal of NGAL.

It is widely reported that HMGB1 is an inflammatory mediator during sepsis. We would also like to know whether it is involved in AKI. During the stage of Hem/sepsis associated AKI, excessive inflammation was a key factor in accelerating the disease. HMGB1 was released by activated macrophages[43]and inhibited inflammation, thereby attenuating the extent of cellular damage and subsequent organ dysfunction[44]. During this stage, HMGB1 continues to act as an anti-inflammatory molecule, which will lead to immune paralysis and poor outcome. In the present study, we found HMGB1 was elevated in AKI and decreased in CD200 deficiency mice. Thus, it could be speculated CD200 modulated AKI via decreasing HMGB1 expression.

Our findings suggest that CD200 may enhance the delivery of anti-inflammatory agents to treat AKI, but inhibition of an inflammatory response and/or preventing the induction of an adaptive response to self-proteins is definitely desirable. In conclusion, CD200 molecule has significant protective effects in AKI. The protective effects were through regulating the levels of serum creatinine, BUN, and inflammatory cytokine production. The potential mechanism may be through inhibiting NGAL and activating HMGB1 signaling pathway. It warranted further study to confirm the molecular mechanism.

Acknowledgements

This work was collectively supported by National Natural Science Foundation of China (81701885) and Talent training program of Shanghai Pudong Hospital (PJ202002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We appreciate pathologist Dr. Yuanyuan Geng’s team for their endeavors on the present work.

Conflicts of interests

All authors declare no conflict of interest here.

Data availability statement

The corresponding author is responsible for materials availability in case of request.

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The protective effect of CD200 on hemorrhage/sepsis-associated acute kidney injury

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