Chinese Journal of Physiology

ORIGINAL ARTICLE
Year
: 2021  |  Volume : 64  |  Issue : 4  |  Page : 194--201

Adropin and spexin hormones regulate the systemic inflammation in adenine-induced chronic kidney failure in rat


Gulsun Memi1, Burak Yazgan2,  
1 Department of Physiology, School of Medicine, Adıyaman University, Adıyaman, Turkey
2 Department of Medical Services and Techniques, Sabuncuoglu Serefeddin Health Services Vocational School; Department of Molecular Medicine, Institute of Health Sciences, Amasya University, Amasya, Turkey

Correspondence Address:
Dr. Gulsun Memi
Department of Physiology, School of Medicine, Adiyaman University, 02040, Adiyaman
Turkey

Abstract

Chronic kidney disease is one of the major global health problems. Chronic renal failure is stimulated by many cytokines and chemokines. Adropin and spexin (SPX) are peptides hormones. These peptides could affect inflammatory conditions, but this is unclear. Due to the limited information, we planned to investigate the impact of adropin and SPX hormones on systemic inflammation in adenine induced chronic kidney failure rat model. Chronic kidney failure was induced by administering adenine hemisulfate. Renal functions were measured by an autoanalyzer. Granulocyte colony-stimulating factor (G-CSF), interferon-gamma (IFN-γ), interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17A, tumor necrosis factor-alpha, Eotaxin, growth-regulated oncogene-alpha, IP-10, monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1α, MIP-2, and RANTES levels were determined by Luminex. We observed an increase in 24-h urine volume and serum creatinine. Blood urea nitrogen (BUN) and urine protein levels were also significantly higher in the chronic kidney failure (CKF) group. Urine protein and 24-h urine volume were reduced with adropin and SPX treatments. Furthermore, G-CSF, IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-17A, and GRO-α significantly increased by CKF induction; however, these cytokines and chemokines significantly decreased by adropin treatment in the CKF group. Furthermore, adropin increased IP-10, MCP-1, MIP-1α, and MIP-2 levels. In addition, SPX treatment had a more limited effect, decreasing only G-CSF, IFN-γ, and IL-5 levels. The combined adropin + SPX treatment significantly reduced G-CSF, IFN-γ, IL-4, IL-5, IL-12, and IL-17A. Furthermore, IP-10, MCP-1, MCP-3, and MIP-2 were significantly increased by these combined treatments. Our findings indicate that renal functions and inflammatory response were modulated by adropin and SPX peptides. These peptides may have protective effects on systemic inflammation and renal failure progression.



How to cite this article:
Memi G, Yazgan B. Adropin and spexin hormones regulate the systemic inflammation in adenine-induced chronic kidney failure in rat.Chin J Physiol 2021;64:194-201


How to cite this URL:
Memi G, Yazgan B. Adropin and spexin hormones regulate the systemic inflammation in adenine-induced chronic kidney failure in rat. Chin J Physiol [serial online] 2021 [cited 2021 Oct 20 ];64:194-201
Available from: https://www.cjphysiology.org/text.asp?2021/64/4/194/190169


Full Text



 Introduction



Chronic kidney disease (CKD) is one of the major global burdens which affects nearly 10%–15% of the population. Chronic kidney failure (CKF) is a severe form of CKD. The causes of it may vary and activate systemic inflammation, tubular damage, sclerosis, and fibrosis are among the most common causes of it.[1] CKF causes an uncontrolled, persistent inflammatory condition that contributes to cardiovascular disease, atherosclerosis, protein energy-wasting, frailty, and accumulation of uremic toxins.[2] Many biological pathways cause chronic inflammation, leading to the release of pro-inflammatory mediators in this uremic milieu. The inflammatory response may continue even after tissue destruction following this inflammatory accumulation.[3] Chronic renal failure (CRF) stimulates primary inflammatory substances, including cytokines such as interferon-gamma (IFN-γ), interleukin-1α (IL-1α), IL-1β, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), and chemokines such as Eotaxin, growth-regulated oncogene-alpha (GRO-α), and monocyte chemoattractant proteins (MCPs).[4],[5] Inflammation biomarkers, such as IL-1β, IL-1 receptor antagonist, IL-6, TNF-α, C-reactive protein (CRP), negatively correlate with kidney functions.[6],[7]

Spexin (SPX), namely neuropeptide Q,[8],[9] is extensively expressed in numerous tissues.[10],[11] This peptide especially regulates various physiologic functions such as gastrointestinal motility, feeding, energy balance, lipid storage, luteinizing hormone release, adrenocortical cell proliferation, nociception and cardiovascular/renal functions, which are arterial blood pressure, salt, and water balance.[12],[13],[14],[15] Current studies have shown that SPX plays a role in the inflammatory response, which is aggravated in mice fed with a fructose-rich diet by lowering levels of TNF-α, IL-1β, and IL-10.[16]

In another study, SPX improved renal oxidative stress and inflammation in obesity-induced renal dysfunction.[17] In addition, recent studies have reported that this hormone affects the inflammatory process, but this aspect is still less clear.[16]

Adropin is a bioactive peptide hormone recently discovered in 2008 by Kumar.[18] It is encoded by Energy Homeostasis Associated Gene expressed on chromosome 9p13.3.[18],[19] Structure of this peptide hormone consists of 76 a.a and has a molecular weight of approximately 4.49 kDa.[20],[21] Adropin is expressed in various tissues such as the brain, cerebellum, umbilical vein, gastrointestinal tract, pancreas, liver, kidney, coronary artery, and heart.[22],[23] Adropin modulates the energy balance of the body consisting of glucose, lipid, and protein metabolism.[21],[24],[25] Accordingly, recent studies have shown that this hormone may play a protective role in the pathogenesis of many diseases such as diabetes, diabetic nephropathy, CKD endothelial dysfunction, heart failure, and cardiovascular disease.[23],[26] Also, some studies have found that adropin has a protective effect in the pathogenesis of these diseases.[27],[28],[29] Moreover, studies have shown that adropin had suppressive effects on atherosclerosis development in human endothelial cells.[30] In this study, we investigated the impact of adropin and SPX hormones on systemic inflammation in adenine induced chronic kidney failure rat model.

 Materials and Methods



Ethics

All experimental animal procedures were approved by the Trakya University Animal Research and Ethics Committee, Edirne, Turkey (Protocol number: TUHADYEK-2016/51).

Study design

Male Sprague-Dawley rats (bodyweight 200–250 g) were housed under standard conditions (12 h light/dark cycle, 65%–70% humidity, 22°C ± 1°C) at Trakya University Animal Research Center, with free access to water and a standard diet. Chronic kidney failure was induced by administering adenine hemisulfate solution daily (600 mg/kg, 5% carboxymethyl cellulose, 1 ml/kg, Sigma-Aldrich, cat. no: A9126) by oral gavage for 10 days.[31],[32] After confirming biochemical measurements of renal damage, animals were divided into four treatment groups.

Experimental groups

The vehicle group (n = 5) was given 5% carboxymethyl cellulose (1 ml/kg, Sigma-Aldrich, cat. no: C9481) daily for 10 days, and then saline was injected intraperitoneally for 4 weeks. CKF group (n = 20) was further divided randomly into four subgroups, namely CKF + saline (saline 1 ml/kg), CKF + adropin (2.1 μg/kg, Phoenix Pharmaceuticals, cat. no: 032–35),[29] CKF + SPX (35 μg/kg, PolyPeptide, cat. no: SC1547),[13] and CKF + adropin + SPX (adropin, 2.1 μg/kg; SPX, 35 μg/kg) and were injected intraperitoneally with an equal dose of one milliliter according to treatments for 4 weeks, 5 days a week. These doses were selected based on the very few publications in which adropin[29] and SPX[13] have been given exogenously.

Following the experimental procedure, all animals were sacrificed under anesthesia (Ketamine, 100 mg/kg; Xylazine, 12.5 mg/kg, i.p.) at the end of 4th week of treatment. Urine and blood samples were collected for renal function and chemokine-cytokine analyses. During the experiment, 24 h urine samples were also collected, and their volume was recorded on day 5 (15th day of the experiment) and at the end of treatments (4th week) following adenine hemisulfate administration after placing rats in a metal metabolic cage. Blood samples were collected in a serum clot activator tube and centrifuged at 2000 g (10 min at 4°C). Serum was taken on the 15th day and at the end of the 4th week of treatment. Serum samples were stored at −80°C for later Luminex analysis.

Biochemical measurements of renal function

The levels of both total protein and creatinine in urine samples and creatinine and BUN in serum samples were measured by an Architect C16000 Clinical Chemistry Analyzer (Abbott Laboratories, Abbott Park, IL, USA). In addition, creatinine clearance and protein/creatinine ratios were calculated.

Measurement of inflammation-related chemokine and cytokines

Levels of inflammation-related chemokine and cytokines in serum samples were determined using the Cytokine and Chemokine 22-Plex Rat ProcartaPlex™ Panel (Invitrogen, cat. no: EPX220-30122-901), which included 14 cytokines, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17A, TNF-α, and 8 chemokines, eotaxin, GRO-α, interferon gamma-inducible protein 10 (IP-10), MCP-1, MCP-3, macrophage inflammatory protein (MIP-1α), and MIP-2, which were found to be regulated on the activation of normal T cell expression and secreted RANTES, according to the manufacturer's instructions. Briefly, the assay used 25 μl of a serum sample to capture an analyte on analyte-specific color-coded magnetic beads coated with capture antibodies. Antibodies were added and then incubated with streptavidin-phycoerythrin, followed by biotinylated detection. Duplicate samples and standards were prepared, and the fluorescence intensity was measured using a Bio-Plex MAGPIX Luminex instrument (Biorad). The levels of these cytokines and chemokines were calculated through Bio-Plex Manager v6.1 software (Biorad, Austin, TX, USA) and xPonent 4.2 (Luminex) software.

Statistics

Data were expressed as means ± SEM. The differences between the groups were evaluated statistically with one-way analysis of variance (ANOVA) and Mann–Whitney U-test for the advanced analysis by GraphPad Prism 6.0 software (San Diego, CA, USA). P < 0.05 was accepted to be statistically significant.

 Results



Biochemical measurements of renal function

We studied biochemical analyzes of the serum and urine samples taken at two different times: on the 15th day when kidney failure occurred and at the end of the experiment, in the 4th week. Adenine-induced chronic kidney failure in all CKF groups developed polyuria and proteinuria. After chronic kidney failure on the 15th day of the experiment, we observed an increase in serum creatinine (V: 0.20 ± 0 mg/mL; CKF: 1.0 ± 0.13 mg/mL) and BUN (V: 39.07 ± 1.17 mg/mL; CKF: 298.4 ± 29.9 mg/mL) levels. Moreover, 24-h urine volume significantly increased by applying adenine hemisulphate solution. In addition, in urine samples, 24-h protein loss was significantly higher in the CKF group (6187 ± 739.3 mg/day) compared to the vehicle (2873 ± 730.6 mg/day) group. To compare protein excretion as a precursor of metabolic breakdown and protein loss as a degree of kidney damage, we calculated the protein/creatinine ratio. As expected, it was positively correlated (r = 0.688) with kidney failure (CKF: 21.16 ± 3.40; V: 3.90 ± 0.24). Urine creatinine levels were low in CKF groups, and these results suggest that it may be developed due to polyuria (24-h urine volume on 15th day was V: 9.35 ± 3.60 vs. CKF: 45.25 ± 10.2 and at the end of 4th week was V: 8.47 ± 2.85 vs. CKF: 50.17 ± 10.89). After adropin and SPX treatment, serum creatinine, BUN, and creatinine clearance did not differ significantly compared to the CKF group. However, adropin treatment reduced urine protein loss (CKF: 461 ± 138.3; CKF + A: 152.9 ± 22.31) and 24-h urine volume (CKF: 50.17 ± 4.44; CKF + A: 27.0 ± 3.37) compared to that in the CKF group. In addition, SPX treatment has reduced effects on urine protein loss (125.3 ± 16.72) and 24-h urine volume (44.2 ± 9.30) [Figure 1].{Figure 1}

Inflammation-related cytokines

Inflammation-related cytokines, such as G-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17A, and TNF-α levels, were measured by the Luminex system, but GM-CSF, IL-1α, and IL-6 could not be detected. As shown in [Figure 2], G-CSF, IFN-γ, IL-4, IL-5, IL-10, IL-12, and IL-17A from these cytokines significantly increased in the CKF group compared to the vehicle group; however, adropin treatment significantly decreased these cytokines compared to the CKF group. Moreover, SPX treatments have shown a more limited effect, decreasing only G-CSF, IFN-γ, and IL-5 levels compared to the CKF group. Furthermore, G-CSF, IFN-γ, IL-4, IL-5, IL-12, and IL-17A levels were significantly reduced by the combined adropin + SPX treatments compared to the CKF group.{Figure 2}

Inflammation-related chemokines

Inflammation-related chemokines, such as Eotaxin, GRO-α, IP-10, MCP-1, MCP-3, MIP-1α, MIP-2, and RANTES levels, were measured by the Luminex system [Figure 3]. Chemokines reacted slightly differently in the CKF group instead of cytokines. While Eotaxin, MCP-3, and RANTES levels significantly decreased, GRO-α level significantly increased compared to the vehicle group. Adropin treatment significantly increased MCP-3 and RANTES levels, but these levels were found to be decreased in the CKF group. Furthermore, adropin increased IP-10, MCP-1, MIP-1α, and MIP-2 levels and significantly decreased GRO-α levels. Moreover, SPX treatment alone did not show significant effects on inflammation-related chemokines. Furthermore, adropin + SPX treatment accelerated the effects of adropin. In particular, IP-10, MCP-1, MCP-3, and MIP-2 were significantly increased by these combined treatments compared to CKF.{Figure 3}

 Discussion



Chronic kidney failure is a progressive disease, and it is clinically important to find effective treatment in the early stages to improve disease progress and survival of patients with CKF. To diagnose CKF, markers of renal injury like serum creatinine and clinical manifestations are commonly used. Adenine-induced CKF has more similar clinical findings, such as increased BUN and serum creatinine in patients with CKF.[33]

For the first time in literature, we investigated the effects of adropin and SPX peptides on chemokine and cytokine profile related to systemic inflammation in the adenine-induced CKF model [Figure 4]. Serum creatinine and BUN levels increased significantly on the 15th day and at the 4th week in this study, while in another study, these increases were observed in the second week of feeding with a diet rich in adenine.[33] In addition, Abellan et al. observed an increase in serum creatinine and BUN levels with unilateral nephrectomy plus a 3-week adenine-supplied diet.[34] Similarly, in this study, there was a decrease in urine creatinine, while a significant increase was observed in urine protein and 24-h urine volume. These results, which are consistent with the literature, show that we have created a moderate chronic renal failure model.[32],[33]{Figure 4}

CKF-induced chronic systemic inflammation and we observed that adropin and SPX regulate some inflammatory and pro-inflammatory cytokines and chemokines. Some inflammatory mediators, like IL-4, IL-10, TGF-β, and lipoxins, and cytokines, like leukotrienes, release as a repair mechanism G-CSF, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17A, TNF-α and chemotactic cytokines (chemokines) such as Eotaxin, GRO-α, IP-10, MCP-1, MCP-3, MIP-1α, MIP-2, RANTES, as a result of chronic inflammatory state in CKF.[3],[35],[36],[37] Damaged renal tissue secretes a wide range of inflammatory mediators.[38] In this study, the most systemic inflammatory cytokines, such as G-CSF, IFN-γ, IL-4, IL-5, IL-10, IL-17A, increased by CKF induction.

In addition, in some diseases, like obesity, macrophage infiltration causes renal injuries, and inflammatory cytokines and chemokines like IL-6, TNF-α, and CRP lead to glomerulosclerosis and tubulointerstitial fibrosis.[39] An anti-inflammatory cytokine, IL-10, reduces inflammation through the down-regulation of pro-inflammatory cytokines and chemokines and reduction of renal inflammatory damage.[40],[41],[42] IL-10 levels were significantly decreased by adropin treatment, so we hypothesized that adropin might have a potential anti-inflammatory role in renal injuries. G-CSF has a potent anti-inflammatory cytokine that exerts its effect by inhibiting TNF-α response.[43] In this study, G-CSF increased in the CKF group, while TNF-α decreased, however, it was not statistically significant. Furthermore, both peptides significantly decreased cytokine response levels of G-CSF, which increased in the CKF group.

IFN-γ treatment, which has an adaptive immunomodulatory role, showed antifibrotic effects on renal disease.[44] We found that IFN-γ levels increased in the CKF group, and both peptides significantly lowered this incremental response. This decrease of IFN, which is a cytokine that stimulates the inflammatory response in CKD, is due to an anti-inflammatory effect of adropin and SPX. IL-17 α is involved in inflammatory diseases such as CKF, and its inhibition is useful in the pathogenesis of acute kidney injury and CKD.[45],[46] We have shown that adropin treatment alone or in combination with SPX reduces inflammatory damage by lowering IL-17A levels.

SPX modulates many physiologic conditions, such as energy balance, lipid storage, and nociception, and cardiovascular/renal function, such as arterial blood pressure and salt and water balance.[14],[15] In our study, SPX did not make any changes in 24 h urine excretion but decreased protein excretion in the CKF group. There are no studies on the effect or mechanism of SPX on kidney failure. Recently, studies indicate that SPX levels affect the inflammatory process. In a study conducted on obese children, it was observed that the amount of SPX decreased and IL-6 increased with obesity.[47] Furthermore, in another study on adolescents with obesity, levels of low SPX and vice versa and high levels of hs-CRP were observed.[48] Similarly, Behrooz et al. found that SPX levels were significantly associated with both anti-inflammatory markers such as IL-10 and pro-inflammatory markers such as IL-1β and hs-CRP in obese children.[49] Moreover, in obese mice, the administration of SPX significantly decreased pro-inflammatory markers, such as IL-6, TNF-α, and IL-1β.[16] In this study, SPX treatment decreases G-CSF, IFN-γ, and IL-5 levels in CKF. These results show that SPX may regulate inflammatory mediators. We evaluated the exogen SPX effects on inflammation, but unfortunately, we did not measure SPX plasma levels or mRNA expression, which is a limitation of this study. Another study found that mRNA expression of SPX significantly decreased in the mice fed with fructose-rich diet, although exogen SPX treatment decreased the inflammatory cytokine levels such as TNF-α, IL-1β, and IL-10.[16]

Adropin regulates energy balance, glucose, lipid, and protein metabolism. Many studies have demonstrated that this hormone may play a protective role in the pathogenesis of several diseases such as diabetes, diabetic nephropathy, CKD, and heart failure.[23],[26] Some studies have indicated that serum adropin concentrations are negatively correlated with renal damage markers, such as BUN and serum creatinine; besides, this hormone positively correlates with eGFR.[28],[48] In this study, we showed that adropin decreased 24-h urine and protein excretion, which are increased by CKF. In addition, adropin alters inflammatory responses and affects the anti-inflammatory process.[19],[29],[50],[51] Ibrahim and Moursi found that serum adropin levels were negatively correlated with the observed renal damage and pro-inflammatory cytokines such as IL-6 and TNF-α in diabetic nephropathic rats; however, they did not make any significant changes in this CKF model.[52] Furthermore, Sato et al. revealed that adropin suppresses THP1 monocyte adhesion to TNF-α induced HUVEC cells, indicating an anti-inflammatory effect of adropin.[28] Also, Gao et al. indicated that the production of IL-1α, IL-1β, IL-6, IL-33, and TNF-α was upregulated by adropin deficiency in adropin knockout mice.[53] However, in this study, adropin downregulated the G-CSF, IFN-γ, IL-4, IL-5, IL-10, IL-12, and IL-17A, which were elevated in the CKF group.

MCP-1, a potent chemokine, is produced in renal cells and downregulated with diabetic kidney disease,[54] similar to our CKF model. Adropin upregulates MCP-1 and MCP-3 levels. These effects may be due to the therapeutic effects of adropin on renal cells.

Previous studies have shown humoral immune response in renal pathologies.[55] Cytokine and chemokine levels such as IL-4, IL-5, IL-6, IL-10, IL-12, IL-17α, G-CSF, and GRO-α increased by CKF induction, indicating the humoral immune response,[56],[57] and most of these cytokine and chemokine levels were attenuated by adropin treatment in this study. Therefore, we think that adropin may have important modulatory effects on the humoral immune response.

Serum eotaxin levels, which play a mediator role in eosinophil chemotaxis, decreased in CKF models, and there was no significant difference between groups with any peptide treatment. This decrease in eotaxin levels in the CKF group is supported by another study showing that eotaxin levels change according to renal disease stages in humans, while it is high in the 3rd stage and decreases in the 5th stage.[55]

Briefly, in this study, we found that adropin significantly increased IP-10, MCP-3, MIP-1, MIP-2, and RANTES levels and significantly decreased GRO-α levels. In addition, while SPX alone did not make any significant changes in G-CSF, IFN-γ, IL-4, IL-5, IL-12, and IL-17A, it increased the positive effects of adropin in the combined treatment of adropin + SPX compared to the use of adropin alone.

The novelty of this study is that we examined the effect of both adropin and SPX exogenously on CKF-induced inflammatory response, and we compared a broad spectrum of inflammatory parameters. Our study has certain limitations. This study is quite preliminary, and the fact that we did not measure the basal serum levels of peptides, even though we had histopathological findings from our previous study,[56] prevents us from reaching a more certain conclusion.

Clinically, the chronic kidney failure process is generally observed from the onset of the disease, and various treatments are applied. This is an experimental study, and no preclinical assessments have been performed. However, the disease model mimics well as it processes the kidney failure stages. Therefore, the results of this study are important for finding the effects of these peptides on inflammatory and biochemical parameters of clinical importance.

 Conclusion



We have shown that adropin or SPX treatment elicits the inflammatory response in chronic renal failure by limiting cytokine and chemokine levels. These findings suggest that these peptides mostly affect anti-inflammatory response to the first defense of leukocytes cytokine expression. Further research is needed to elucidate the mechanisms of action of these peptides on CKF.

Acknowledgment

Authors would like to thank the Marmara University Gastroenterology Institute for their kind understanding of using their facilities. Author contributions: Gulsun Memi: conceptualization, investigation, formal analysis, project administration, funding acquisition, writing, review and editing; Burak Yazgan: conceptualization, investigation, formal analysis, writing, review and editing.

Financial support and sponsorship

This work was supported by Trakya University Research Fund (grant number: 2018/118).

Conflicts of interest

There are no conflicts of interest.

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