https://doi.org/10.4081/ejh.2022.3412
Transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) ameliorates sepsis-associated acute kidney injury by maintaining mitochondrial homeostasis and improving the mitochondrial function
Submitted: 24 March 2022
Accepted: 19 May 2022
Published: 21 June 2022
Accepted: 19 May 2022
Abstract Views: 1448
PDF: 981
HTML: 19
HTML: 19
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Mitochondrial dysfunction has a role in sepsis-associated acute kidney injury (S-AKI), so the restoration of normal mitochondrial homeostasis may be an effective treatment strategy. Transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) is a main regulator of cell-redox homeostasis, and recent studies reported that NRF2 activation helped to preserve mitochondrial morphology and function under conditions of stress. However, the role of NRF2 in the process of S-AKI is still not well understood. The present study investigated whether NRF2 regulates mitochondrial homeostasis and influences mitochondrial function in S-AKI. We demonstrated activation of NRF2 in an in vitro model: lipopolysaccharide (LPS) challenge of ductal epithelial cells of rat renal tubules (NRK-52e cells), and an in vivo model: cecal ligation and puncture (CLP) of rats. Over-expression of NRF2 attenuated oxidative stress, apoptosis, and the inflammatory response; enhanced mitophagy and mitochondrial biogenesis; and mitigated mitochondrial damage in the in vitro model. In vivo experiments showed that rats treated with an NRF2 agonist had higher adenosine triphosphate (ATP) levels, lower blood urea nitrogen and creatinine levels, fewer renal histopathological changes, and higher expression of mitophagy-related proteins [PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PRKN), microtubule-associated protein 1 light chain 3 II (LC3 II)] and mitochondrial biogenesis-related proteins [peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) and mitochondrial transcription factor A (TFAM)]. Electron microscopy of kidney tissues showed that mitochondrial damage was alleviated by treatment with an NRF2 agonist, and the opposite response occurred upon treatment with an NRF2 antagonist. Overall, our findings suggest that mitochondria have an important role in the pathogenesis of S-AKI, and that NRF2 activation restored mitochondrial homeostasis and function in the presence of this disease. This mitochondrial pathway has the potential to be a novel therapeutic target for the treatment of S-AKI.
Kellum JA, Romagnani P, Ashuntantang G, Ronco C, Zarbock A, Anders HJ. Acute kidney injury. Nat Rev Dis Primers 2021;7:52.
DOI: https://doi.org/10.1038/s41572-021-00284-z
Liu N, Zhang Z, Hong Y, Li B, Cai H, Zhao H, et al. Protocol for a prospective observational study on the association of variables obtained by contrast-enhanced ultrasonography and sepsis-associated acute kidney injury. BMJ Open 2019;9:e023981.
DOI: https://doi.org/10.1136/bmjopen-2018-023981
Peters E, Antonelli M, Wittebole X, Nanchal R, François B, Sakr Y, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from The Intensive Care Over Nations audit. Crit Care 2018;22:188.
DOI: https://doi.org/10.1186/s13054-018-2112-z
Dedionisio A. Establishing a new model of endotoxemia-associated acute kidney injury in zebrafish. University of Pittsburgh; 2020. Available from: http://d-scholarship.pitt.edu/39642/
Koyner JL, Chawla LS, Bihorac A, Gunnerson KJ, Schroeder R, Demirjian S, et al. Performance of a standardized clinical assay for urinary CC motif chemokine ligand 14 (CCL14) for persistent severe acute kidney injury. Kidney360 2022:3:1-38.
DOI: https://doi.org/10.34067/KID.0008002021
Bhatia D, Capili A, Choi ME. Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches. Kidney Res Clin Pract 2020;39:244-58.
DOI: https://doi.org/10.23876/j.krcp.20.082
Li Y, Nourbakhsh N, Pham H, Tham R, Zuckerman JE, Singh P. Evolution of altered tubular metabolism and mitochondrial function in sepsis-associated acute kidney injury. Am J Physiol Renal Physiol 2020;319:F229-44.
DOI: https://doi.org/10.1152/ajprenal.00390.2019
Gkikas I, Palikaras K, Tavernarakis N. The role of mitophagy in innate immunity. Front Immunol 2018;9:1283.
DOI: https://doi.org/10.3389/fimmu.2018.01283
Mohanty A, Tiwari-Pandey R, Pandey NR. Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response. J Cell Commun Signal 2019;13:303-18.
DOI: https://doi.org/10.1007/s12079-019-00507-9
Gómez H, Kellum JA. Sepsis-induced acute kidney injury. Curr Opin Crit Care 2016;22:546-53.
DOI: https://doi.org/10.1097/MCC.0000000000000356
Thiagarajan D. Phospholipid related antigens and protective mechanisms: Implications for cardiovascular diseases, human autoimmunity and inflammation [D]. PhD Thesis, Karolinska Institutet; 2019. Available from: https://openarchive.ki.se/xmlui/handle/10616/46633
Karkossa I, Raps S, von Bergen M, Schubert K. Systematic review of multi-omics approaches to investigate toxicological effects in macrophages. Int J Mol Sci 2020;21:9371.
DOI: https://doi.org/10.3390/ijms21249371
Kraft BD, Chen L, Suliman HB, Piantadosi CA, Welty-Wolf KE. Peripheral blood mononuclear cells demonstrate mitochondrial damage clearance during sepsis. Crit Care Med 2019;47:651-8.
DOI: https://doi.org/10.1097/CCM.0000000000003681
Hara H, Kuwano K, Araya J. Mitochondrial quality control in COPD and IPF. Cells 2018;7:86.
DOI: https://doi.org/10.3390/cells7080086
Sedlackova L, Korolchuk VI. Mitochondrial quality control as a key determinant of cell survival. Biochim Biophys Acta Mol Cell Res 2019;1866:575-87.
DOI: https://doi.org/10.1016/j.bbamcr.2018.12.012
Tang C, Cai J, Yin XM, Weinberg JM, Venkatachalam MA, Dong Z. Mitochondrial quality control in kidney injury and repair. Nat Rev Nephrol 2021;17:299-318.
DOI: https://doi.org/10.1038/s41581-020-00369-0
Franco-Iborra S, Vila M, Perier C. Mitochondrial quality control in neurodegenerative diseases: Focus on Parkinson's disease and Huntington's disease. Front Neurosci 2018;12:342.
DOI: https://doi.org/10.3389/fnins.2018.00342
Wu Y, Yao YM, Lu ZQ. Mitochondrial quality control mechanisms as potential therapeutic targets in sepsis-induced multiple organ failure. J Mol Med (Berl) 2019;97:451-62.
DOI: https://doi.org/10.1007/s00109-019-01756-2
Zhu J, Zhang S, Geng Y, Song Y. Transient receptor potential ankyrin 1 protects against sepsis-induced kidney injury by modulating mitochondrial biogenesis and mitophagy. Am J Transl Res 2018;10:4163-72.
Liu JX, Yang C, Zhang WH, Su HY, Liu ZJ, Pan Q, et al. Disturbance of mitochondrial dynamics and mitophagy in sepsis-induced acute kidney injury. Life Sci 2019;235:116828.
DOI: https://doi.org/10.1016/j.lfs.2019.116828
Abrescia P, Treppiccione L, Rossi M, Bergamo P. Modulatory role of dietary polyunsaturated fatty acids in Nrf2-mediated redox homeostasis. Prog Lipid Res 2020;80:101066.
DOI: https://doi.org/10.1016/j.plipres.2020.101066
Dai X, Yan X, Wintergerst KA, Cai L, Keller BB, Tan Y. Nrf2: Redox and metabolic regulator of stem cell state and function. Trends Mol Med 2020;26:185-200.
DOI: https://doi.org/10.1016/j.molmed.2019.09.007
Surai PF, Kochish II, Fisinin VI, Kidd MT. Antioxidant defence systems and oxidative stress in poultry biology: An update. Antioxidants (Basel) 2019;8:235.
DOI: https://doi.org/10.3390/antiox8070235
Liu Q, Zhang F, Zhang X, Cheng R, Ma JX, Yi J, et al. Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation. Mol Cell Biochem 2018;445:105-15.
DOI: https://doi.org/10.1007/s11010-017-3256-x
Liu JX, Yang C, Liu ZJ, Su HY, Zhang WH, Pan Q, et al. Protection of procyanidin B2 on mitochondrial dynamics in sepsis associated acute kidney injury via promoting Nrf2 nuclear translocation. Aging (Albany NY) 2020;12:15638-55.
DOI: https://doi.org/10.18632/aging.103726
Huang Y, Zhou F, Shen C, Wang H, Xiao Y. LBP reduces theinflammatory injuryof kidney in septic rat and regulates the Keap1-Nrf2∕ARE signaling pathway1. Acta Cir Bras 2019;34:e20190010000003.
DOI: https://doi.org/10.1590/s0102-865020190010000003
Wu Q, Liu LT, Wang XY, Lang ZF, Meng XH, Guo SF, et al. Lycium barbarum polysaccharides attenuate kidney injury in septic rats by regulating Keap1-Nrf2/ARE pathway. Life Sci 2020;242:117240.
DOI: https://doi.org/10.1016/j.lfs.2019.117240
Murata H, Takamatsu H, Liu S, Kataoka K, Huh NH, Sakaguchi M. NRF2 regulates PINK1 expression under oxidative stress conditions. PLoS One 2015;10:e0142438.
DOI: https://doi.org/10.1371/journal.pone.0142438
Piantadosi CA, Carraway MS, Babiker A, Suliman HB. Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 2008;103:1232-40.
DOI: https://doi.org/10.1161/01.RES.0000338597.71702.ad
Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington: the National Academies Press; 2011. Available from: https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf
Toscano MG, Ganea D, Gamero AM. Cecal ligation puncture procedure. J Vis Exp 2011;51:2860.
DOI: https://doi.org/10.3791/2860
Sukumari-Ramesh S, Alleyne CH Jr. Post-Injury administration of tert-butylhydroquinone attenuates acute neurological injury after intracerebral hemorrhage in mice. J Mol Neurosci 2016;58:525-31.
DOI: https://doi.org/10.1007/s12031-016-0722-y
Xian P, Hei Y, Wang R, Wang T, Yang J, Li J, et al. Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice. Theranostics 2019;9:5956-75.
DOI: https://doi.org/10.7150/thno.33872
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.
DOI: https://doi.org/10.1016/j.exger.2017.10.021
Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int 2019;96:1083-99.
DOI: https://doi.org/10.1016/j.kint.2019.05.026
Jacobs R, Honore PM, Joannes-Boyau O, Boer W, De Regt J, De Waele E, et al. Septic acute kidney injury: the culprit is inflammatory apoptosis rather than ischemic necrosis. Blood Purif 2011;32:262-5.
DOI: https://doi.org/10.1159/000330244
Neyra JA, Li X, Canepa-Escaro F, Adams-Huet B, Toto RD, Yee J, et al. Cumulative fluid balance and mortality in septic patients with or without acute kidney injury and chronic kidney disease. Crit Care Med 2016;44:1891-900.
DOI: https://doi.org/10.1097/CCM.0000000000001835
Chua HR, Wong WK, Ong VH, Agrawal D, Vathsala A, Tay HM, et al. Extended mortality and chronic kidney disease after septic acute kidney injury. J Intensive Care Med 2020;35:527-35.
DOI: https://doi.org/10.1177/0885066618764617
Arulkumaran N, Pollen S, Greco E, Courtneidge H, Hall AM, Duchen MR, et al. Renal Tubular cell mitochondrial dysfunction occurs despite preserved renal oxygen delivery in experimental septic acute kidney injury. Crit Care Med 2018;46:e318-25.
DOI: https://doi.org/10.1097/CCM.0000000000002937
West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011;472:476-80.
DOI: https://doi.org/10.1038/nature09973
Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007;87:99-163.
DOI: https://doi.org/10.1152/physrev.00013.2006
Qiu YH, Zhang TS, Wang XW, Wang MY, Zhao WX, Zhou HM, et al. Mitochondria autophagy: a potential target for cancer therapy. J Drug Target 2021;29:576-91.
DOI: https://doi.org/10.1080/1061186X.2020.1867992
Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 2004;286:R491-7.
DOI: https://doi.org/10.1152/ajpregu.00432.2003
Holmström KM, Baird L, Zhang Y, Hargreaves I, Chalasani A, Land JM, et al. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol Open 2013;2:761-70.
DOI: https://doi.org/10.1242/bio.20134853
Fetoni AR, Paciello F, Rolesi R, Paludetti G, Troiani D. Targeting dysregulation of redox homeostasis in noise-induced hearing loss: Oxidative stress and ROS signaling. Free Radic Biol Med 2019;135:46-59.
DOI: https://doi.org/10.1016/j.freeradbiomed.2019.02.022
Lee DY, Song MY, Kim EH. Role of oxidative stress and Nrf2/KEAP1 signaling in colorectal cancer: Mechanisms and Therapeutic perspectives with phytochemicals. Antioxidants (Basel) 2021;10:743.
DOI: https://doi.org/10.3390/antiox10050743
Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 2009;284:13291-5.
DOI: https://doi.org/10.1074/jbc.R900010200
Gui Y, Yang Y, Xu D, Tao S, Li J. Schisantherin A attenuates sepsis-induced acute kidney injury by suppressing inflammation via regulating the NRF2 pathway. Life Sci 2020;258:118161.
DOI: https://doi.org/10.1016/j.lfs.2020.118161
Mendonca P, Soliman KFA. Flavonoids activation of the transcription factor Nrf2 as a hypothesis approach for the prevention and modulation of SARS-CoV-2 infection severity. Antioxidants (Basel) 2020;9:659.
DOI: https://doi.org/10.3390/antiox9080659
Scorrano L. Opening the doors to cytochrome c: changes in mitochondrial shape and apoptosis. Int J Biochem Cell Biol 2009;41:1875-83.
DOI: https://doi.org/10.1016/j.biocel.2009.04.016
McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS, Oorschot V, et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 2018;359:eaao6047.
DOI: https://doi.org/10.1126/science.aao6047
Kuznetsov AV, Kehrer I, Kozlov AV, Haller M, Redl H, Hermann M, et al. Mitochondrial ROS production under cellular stress: comparison of different detection methods. Anal Bioanal Chem 2011;400:2383-90.
DOI: https://doi.org/10.1007/s00216-011-4764-2
Dai XG, Xu W, Li T, Lu JY, Yang Y, Li Q, et al. Involvement of phosphatase and tensin homolog-induced putative kinase 1-Parkin-mediated mitophagy in septic acute kidney injury. Chin Med J (Engl) 2019;132:2340-7.
DOI: https://doi.org/10.1097/CM9.0000000000000448
Gao Y, Dai X, Li Y, Li G, Lin X, Ai C, et al. Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury. J Transl Med 2020;18:114.
DOI: https://doi.org/10.1186/s12967-020-02283-2
Zhang Z, Chen Z, Liu R, Liang Q, Peng Z, Yin S, et al. Bcl-2 Proteins regulate mitophagy in lipopolysaccharide-induced acute lung injury via PINK1/parkin signaling pathway. Oxid Med Cell Longev 2020;2020:6579696.
DOI: https://doi.org/10.1155/2020/6579696
Xiao L, Xu X, Zhang F, Wang M, Xu Y, Tang D, et al. The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biol 2017;11:297-311.
DOI: https://doi.org/10.1016/j.redox.2016.12.022
Yan C, Gong L, Chen L, Xu M, Abou-Hamdan H, Tang M, et al. PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 2020;16:419-34.
DOI: https://doi.org/10.1080/15548627.2019.1628520
Tanaka K. The PINK1-parkin axis: An overview. Neurosci Res 2020;159:9-15.
DOI: https://doi.org/10.1016/j.neures.2020.01.006
Piantadosi CA, Withers CM, Bartz RR, MacGarvey NC, Fu P, Sweeney TE, et al. Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. J Biol Chem 2011;286:16374-85.
DOI: https://doi.org/10.1074/jbc.M110.207738
Athale J, Ulrich A, MacGarvey NC, Bartz RR, Welty-Wolf KE, Suliman HB, et al. Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice. Free Radic Biol Med 2012;53:1584-94.
DOI: https://doi.org/10.1016/j.freeradbiomed.2012.08.009
How to Cite
Chen, Z., Wang, H., Hu, B., Chen, X., Zheng, M., Liang, L., … Zeng, Q. (2022). Transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) ameliorates sepsis-associated acute kidney injury by maintaining mitochondrial homeostasis and improving the mitochondrial function. European Journal of Histochemistry, 66(3). https://doi.org/10.4081/ejh.2022.3412
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Zhiyang Wang, Jing Li, Ziwei Liu, Ling Yue, Nrf2 as a novel diagnostic biomarker for papillary thyroid carcinoma , European Journal of Histochemistry: Vol. 67 No. 2 (2023)
- J. Hansson, A.E. Ericsson, H. Axelson, M.E. Johansson, Species diversity regarding the presence of proximal tubular progenitor cells of the kidney , European Journal of Histochemistry: Vol. 60 No. 1 (2016)
- Zhi Wang, Guihua Jian, Teng Chen, Yiping Chen, Junhui Li, Niansong Wang, The Qi-Bang-Yi-Shen formula ameliorates renal dysfunction and fibrosis in rats with diabetic kidney disease via regulating PI3K/AKT, ERK and PPARγ signaling pathways , European Journal of Histochemistry: Vol. 67 No. 1 (2023)
- Zongfang Ren, Haoren Tang, Linjun Wan, Xing Liu, Ning Tang, Lingling Wang, Zhenhui Guo, Swertianolin ameliorates immune dysfunction in sepsis via blocking the immunosuppressive function of myeloid-derived suppressor cells , European Journal of Histochemistry: Vol. 65 No. 3 (2021)
- I. Golic, K. Velickovic, M. Markelic, A. Stancic, A. Jankovic, M. Vucetic, V. Otasevic, B. Buzadzic, B. Korac, A. Korac, Calcium-induced alteration of mitochondrial morphology and mitochondrial-endoplasmic reticulum contacts in rat brown adipocytes , European Journal of Histochemistry: Vol. 58 No. 3 (2014)
- Jun Lin, Liping Jiang, Kun Guo, Ning Feng, Decreased VEGFA alleviates the symptoms of LPS-induced sepsis in a mouse model by inhibiting glycolysis and thereby regulating the polarization of macrophages , European Journal of Histochemistry: Vol. 67 No. 1 (2023)
- Yuejuan Cao, Li Cui, Shaoyong Tuo, Hongze Liu, Shaonan Cui, Resveratrol mediates mitochondrial function through the sirtuin 3 pathway to improve abnormal metabolic remodeling in atrial fibrillation , European Journal of Histochemistry: Vol. 68 No. 2 (2024)
- Qian Hu, Ran Tao, Xiaoyun Hu, Haibo Wu, Jianjun Xu, Effects of piperlonguminine on lung injury in severe acute pancreatitis via the TLR4/NF-κB pathway , European Journal of Histochemistry: Vol. 67 No. 2 (2023)
- Liuchang Feng, Zaoqiang Lin, Zeyong Tang, Lin Zhu, Shu Xu, Xi Tan, Xinyuan Wang, Jianling Mai, Qinxiang Tan, Emodin improves renal fibrosis in chronic kidney disease by regulating mitochondrial homeostasis through the mediation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) , European Journal of Histochemistry: Vol. 68 No. 2 (2024)
- Liying Shen, Kongjie Lu, Zhenfeng Chen, Yingwei Zhu, Cong Zhang, Li Zhang, Pre-treatment with galectin-1 attenuates lipopolysaccharide-induced myocarditis by regulating the Nrf2 pathway , European Journal of Histochemistry: Vol. 67 No. 4 (2023)
You may also start an advanced similarity search for this article.
Publication Facts
Metric
This article
Other articles
Peer reviewers
3
2.4
Reviewer profiles N/A
Author statements
Author statements
This article
Other articles
Data availability
N/A
16%
External funding
N/A
32%
Competing interests
N/A
11%
Metric
This journal
Other journals
Articles accepted
57%
33%
Days to publication
88
145
- Editor & editorial board
- profiles
- Academic society
- N/A
- Publisher
- PAGEPress Publications, Pavia, Italy
To learn about these publication facts, click 
PF is maintained by the Public Knowledge Project
