Effects of mesencephalic astrocyte-derived neurotrophic factor on sepsis-associated acute kidney injury

doi:10.5847/wjem.j.1920-8642.2023.077

Abstract

Abstract:

BACKGROUND: To determine the protective role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in regulating sepsis-associated acute kidney injury (S-AKI).
METHODS: A total of 96 mice were randomly divided into the control group, control+MANF group, S-AKI group, and S-AKI+MANF group. The S-AKI model was established by injecting lipopolysaccharide (LPS) at 10 mg/kg intraperitoneally. MANF (200 μg/kg) was administered to the control+MANF and S-AKI+MANF groups. An equal dose of normal saline was administered daily intraperitoneally in the control and S-AKI groups. Serum and kidney tissue samples were obtained for biochemical analysis. Western blotting was used to detect the protein expression of MANF in the kidney, and enzyme-linked immunosorbent assay (ELISA) was used to determine expression of MANF in the serum, pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]). Serum creatinine (SCr), and blood urea nitrogen (BUN) were examined using an automatic biochemical analyzer. In addition, the kidney tissue was observed for pathological changes by hematoxylin-eosin staining. The comparison between two groups was performed by unpaired Student’s t-test, and statistics among multiple groups were carried out using Tukey’s post hoc test following one-way analysis of variance (ANOVA). A P-value <0.05 was considered statistically significant.
RESULTS: At the early stage of S-AKI, MANF in the kidney tissue was up-regulated, but with the development of the disease, it was down-regulated. Renal function was worsened in the S-AKI group, and TNF-α and IL-6 were elevated. The administration of MANF significantly alleviated the elevated levels of SCr and BUN and inhibited the expression of TNF-α and IL-6 in the kidney. The pathological changes were more extensive in the S-AKI group than in the S-AKI+MANF group.
CONCLUSION: MANF treatment may significantly alleviate renal injury, reduce the inflammatory response, and alleviate or reverse kidney tissue damage. MANF may have a protective effect on S-AKI, suggesting a potential treatment for S-AKI.

Key words: Sepsis-associated acute kidney injury, Mesencephalic astrocyte-derived neurotrophic factor, Renal function, Cytokines, Endoplasmic reticulum stress

Saifeng Chen, Xuewei Hao, Guo Chen, Guorong Liu, Xiaoyan Yuan, Peiling Shen, Dongfeng Guo. Effects of mesencephalic astrocyte-derived neurotrophic factor on sepsis-associated acute kidney injury[J]. World Journal of Emergency Medicine, 2023, 14(5): 386-392.

Figures/Tables 2

References 38

1	Yu SY, Ge ZZ, Xiang J, Gao YX, Lu X, Walline JH, et al. Is rosuvastatin protective against sepsis-associated encephalopathy? A secondary analysis of the SAILS trial. World J Emerg Med. 2022; 13(5):367-72.
2	Kopec G, Collin M, Das A. Application of Kaiser Sepsis Calculator in culture-positive infants with early onset sepsis. World J Pediatr. 2021; 17(4):429-33. doi: 10.1007/s12519-021-00446-9
3	Prachanukool T, Sanguanwit P, Yuksen KSC, Vichiensanth P. Initial venous lactate levels as a predictor of mortality in severe sepsis: a single-center retrospective cohort study. World J Emerg Med. 2022; 13(5):396-9. doi: 10.5847/wjem.j.1920-8642.2022.078 pmid: 36119767
4	Montomoli J, Donati A, Ince C. Acute kidney injury and fluid resuscitation in septic patients: are we protecting the kidney? Nephron. 2019; 143(3):170-3. doi: 10.1159/000501748
5	Goriki Y, Tanaka A, Nishihira K, Kuriyama N, Shibata Y, Node K. A novel prediction model of acute kidney injury based on combined blood variables in STEMI. JACC Asia. 2021; 1(3):372-81. doi: 10.1016/j.jacasi.2021.07.013 pmid: 36341223
6	Zhang D, Lu H, Hou W, Bai Y, Wu X. Effect of miR-132-3p on sepsis-induced acute kidney injury in mice via regulating HAVCR1/KIM-1. Am J Transl Res. 2021; 13(7):7794-803. pmid: 34377256
7	Kothari NR, Gipson GT, Kidd JM. From surviving sepsis to surviving sepsis-associated acute kidney injury: focusing on risk stratification of acute kidney injury/acute kidney disease after sepsis. Kidney Med. 2021; 3(4):475-7. doi: 10.1016/j.xkme.2021.06.002
8	Chen HG, Han HZ, Li Y, Yu YH, Xie KL. Hydrogen alleviated organ injury and dysfunction in sepsis: the role of cross-talk between autophagy and endoplasmic reticulum stress: experimental research. Int Immunopharmacol. 2020; 78:106049. doi: 10.1016/j.intimp.2019.106049
9	Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006; 7(9):880-5. doi: 10.1038/sj.embor.7400779 pmid: 16953201
10	Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. Int J Mol Sci. 2019; 20(21):5376. doi: 10.3390/ijms20215376
11	Niu Y, Chen Y, Sun P, Wang Y, Luo J, Ding Y, et al. Intragastric and atomized administration of canagliflozin inhibit inflammatory cytokine storm in lipopolysaccharide-treated sepsis in mice: a potential COVID-19 treatment. Int Immunopharmacol. 2021; 96:107773. doi: 10.1016/j.intimp.2021.107773
12	Lindahl M, Saarma M, Lindholm P. Unconventional neurotrophic factors CDNF and MANF: structure, physiological functions and therapeutic potential. Neurobiol Dis. 2017; 97:90-102. doi: S0969-9961(16)30171-1 pmid: 27425895
13	Kim Y, Lee H, Manson SR, Lindahl M, Evans B, Miner JH, et al. Mesencephalic astrocyte-derived neurotrophic factor as a urine biomarker for endoplasmic reticulum stress-related kidney diseases. J Am Soc Nephrol. 2016; 27(10):2974-82. pmid: 26940092
14	Wang Y, Wen W, Li H, Clementino M, Xu H, Xu M, et al. MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress. Neurobiol Dis. 2021; 148:105216. doi: 10.1016/j.nbd.2020.105216
15	Xu S, Di Z, He Y, Wang R, Ma Y, Sun R, et al. Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Aβ toxicity via attenuating Aβ-induced endoplasmic reticulum stress. J Neuroinflammation. 2019; 16(1):35. doi: 10.1186/s12974-019-1429-0
16	Danilova T, Galli E, Pakarinen E, Palm E, Lindholm P, Saarma M, et al. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is highly expressed in mouse tissues with metabolic function. Front Endocrinol (Lausanne). 2019; 10:765. doi: 10.3389/fendo.2019.00765
17	Danilova T, Lindahl M. Emerging roles for mesencephalic astrocyte-derived neurotrophic factor (MANF) in pancreatic beta cells and diabetes. Front Physiol. 2018; 9:1457. doi: 10.3389/fphys.2018.01457 pmid: 30386256
18	Wang P, Yang Y, Pang G, Zhang C, Wei C, Tao X, et al. Hepatocyte-derived MANF is protective for rifampicin-induced cholestatic hepatic injury via inhibiting ATF4-CHOP signal activation. Free Radic Biol Med. 2021; 162:283-97. doi: 10.1016/j.freeradbiomed.2020.10.028
19	Wu H, Li H, Wen W, Wang Y, Xu H, Xu M, et al. MANF protects pancreatic acinar cells against alcohol-induced endoplasmic reticulum stress and cellular injury. J Hepatobiliary Pancreat Sci. 2021; 28(10):883-92. doi: 10.1002/jhbp.928 pmid: 33644980
20	Glembotski CC, Thuerauf DJ, Huang CQ, Vekich JA, Gottlieb RA, Doroudgar S. Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion. J Biol Chem. 2012; 287(31):25893-904. doi: 10.1074/jbc.M112.356345 pmid: 22637475
21	Ma S, Evans RG, Iguchi N, Tare M, Parkington HC, Bellomo R, et al. Sepsis-induced acute kidney injury: a disease of the microcirculation. Microcirculation. 2019; 26(2):e12483. doi: 10.1111/micc.2019.26.issue-2
22	Fu J, Nchambi KM, Wu H, Luo X, An X, Liu D. Liraglutide protects pancreatic β cells from endoplasmic reticulum stress by upregulating MANF to promote autophagy turnover. Life Sci. 2020; 252:117648. doi: 10.1016/j.lfs.2020.117648
23	Li L, Peng X, Guo L, Zhao Y, Cheng Q. Sepsis causes heart injury through endoplasmic reticulum stress-mediated apoptosis signaling pathway. Int J Clin Exp Pathol. 2020; 13(5):964-71.
24	Gao FJ, Zhang SH, Li TT, Wu JH, Wu Q. Expression and distribution of mesencephalic astrocyte-derived neurotrophic factor in the retina and optic nerve. Front Hum Neurosci. 2017; 10:686. doi: 10.3389/fpsyg.2019.00686
25	Yang Y, Wang P, Zhang C, Huang F, Pang G, Wei C, et al. Hepatocyte-derived MANF alleviates hepatic ischaemia-reperfusion injury via regulating endoplasmic reticulum stress-induced apoptosis in mice. Liver Int. 2021; 41(3):623-39. doi: 10.1111/liv.14697 pmid: 33064897
26	Brochard L, Abroug F, Brenner M, Broccard AF, Danner RL, Ferrer M, et al. An Official ATS/ERS/ESICM/SCCM/SRLF Statement: prevention and management of acute renal failure in the ICU patients: an international consensus conference in intensive care medicine. Am J Respir Crit Care Med. 2010; 181(10):1128-55. doi: 10.1164/rccm.200711-1664ST
27	Liu H, Wang L, Weng X, Chen H, Du Y, Diao C, et al. Inhibition of Brd4 alleviates renal ischemia/reperfusion injury-induced apoptosis and endoplasmic reticulum stress by blocking FoxO4-mediated oxidative stress. Redox Biol. 2019; 24:101195. doi: 10.1016/j.redox.2019.101195
28	Li WY, Li W, Leng Y, Xiong YH, Xia ZY. Ferroptosis is involved in diabetes myocardial ischemia/reperfusion injury through endoplasmic reticulum stress. DNA Cell Biol. 2020; 39(2):210-25. doi: 10.1089/dna.2019.5097 pmid: 31809190
29	Hadley G, Neuhaus AA, Couch Y, Beard DJ, Adriaanse BA, Vekrellis K, et al. The role of the endoplasmic reticulum stress response following cerebral ischemia. Int J Stroke. 2018; 13(4):379-90. doi: 10.1177/1747493017724584 pmid: 28776456
30	Trychta KA, Bäck S, Henderson MJ, Harvey BK. KDEL receptors are differentially regulated to maintain the ER proteome under calcium deficiency. Cell Rep. 2018; 25(7):1829-40.e6. doi: S2211-1247(18)31644-9 pmid: 30428351
31	Allen TM, Hansen CB, Guo LS. Subcutaneous administration of liposomes: a comparison with the intravenous and intraperitoneal routes of injection. Biochim Biophys Acta. 1993; 1150(1):9-16. pmid: 8334142
32	Wang X, Li W, Zhou Q, Li J, Wang X, Zhang J, et al. MANF promotes diabetic corneal epithelial wound healing and nerve regeneration by attenuating hyperglycemia-induced endoplasmic reticulum stress. Diabetes. 2020; 69(6):1264-78. doi: 10.2337/db19-0835 pmid: 32312869
33	Zhang J, Tong W, Sun H, Jiang M, Shen Y, Liu Y, et al. Nrf2-mediated neuroprotection by MANF against 6-OHDA-induced cell damage via PI3K/AKT/GSK3β pathway. Exp Gerontol. 2017; 100:77-86.
34	Lewington AJP, Cerdá J, Mehta RL. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int. 2013; 84(3):457-67. doi: 10.1038/ki.2013.153 pmid: 23636171
35	Bucaloiu ID, Lester Kirchner H, Norfolk ER, Hartle JE II, Perkins RM. Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney Int. 2012; 81(5):477-85. doi: 10.1038/ki.2011.405 pmid: 22157656
36	Kramann R, Tanaka M, Humphreys BD. Fluorescence microangiography for quantitative assessment of peritubular capillary changes after AKI in mice. J Am Soc Nephrol. 2014; 25(9):1924-31. doi: 10.1681/ASN.2013101121 pmid: 24652794
37	Sato Y, Yanagita M. Immune cells and inflammation in AKI to CKD progression. Am J Physiol Renal Physiol. 2018; 315(6): F1501-F1512. doi: 10.1152/ajprenal.00195.2018
38	Sharfuddin AA, Molitoris BA. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol. 2011; 7(4):189-200. doi: 10.1038/nrneph.2011.16 pmid: 21364518

[1]	Yi-wen Fan, Shao-wei Jiang, Jia-meng Chen, Hui-qi Wang, Dan Liu, Shu-ming Pan, Cheng-jin Gao. A pulmonary source of infection in patients with sepsis-associated acute kidney injury leads to a worse outcome and poor recovery of kidney function [J]. World Journal of Emergency Medicine, 2020, 11(1): 18-26.
[2]	Zhi-wei Liu, Hai-ying Wang, Lan Guan, Bin Zhao. Regulatory effects of hydrogen sulfide on alveolar epithelial cell endoplasmic reticulum stress in rats with acute lung injury [J]. World Journal of Emergency Medicine, 2015, 6(1): 67-73.
[3]	Yan-jun Qin, Xin-liang Zhang, Yue-qing Yu, Xiao-hua Bian, Shi-min Dong. Cardioprotective effect of erythropoietin on sepsis-induced myocardial injury in rats [J]. World Journal of Emergency Medicine, 2013, 4(3): 215-223.
[4]	Lu-yi Liu, Yong-jian Zhu, Xiao-li Li, Ya-feng Liang, Zuo-peng Liang, Yong-hong Xia. Blood hemoperfusion with resin adsorption combined continuous veno-venous hemofiltration for patients with multiple organ dysfunction syndrome [J]. World Journal of Emergency Medicine, 2012, 3(1): 44-48.