IRX1 ameliorates sepsis-induced acute kidney injury in mice by promoting CXCL14

Main Article Content

Jie Zhang
Yanlin Yue
Yunyan Ma


acute kidney injury, CXCL14, Inflammation, IRX1, sepsis


Background: Sepsis-induced acute kidney injury is a general critical complication having high relevance to kidney inflammation. In spite of advances in clinical and critical care, the specific and effective therapies for acute kidney injury are still insufficient. The present study aimed to investigate the protective effect of Iroquois homeobox genes (IRX) on sepsis-induced kidney dysfunction in mice.

Methods: In order to gain insight into sepsis-related actions in acute kidney injury, the cecal puncture-induced kidney injury animal model was established. The hematoxylin and eosin staining was used to measure the pathology of kidney tissues. The kidney function-related biomarkers, including neutrophil gelatinase-associated lipocalin, creatinine, kidney injury molecule-1, blood urea nitrogen, and inflammatory cytokines, which included tumor necrosis factor α, interleukin 1β (IL-1β), IL-6, and monocyte chemotactic protein 1, were detected by automated biochemical analyzer or their corresponding test kits. The protein expression was measured using Western blot analysis, and the apoptotic rate of kidney tissue was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling assay.

Results: The present study revealed the protective ability of IRX1 in sepsis-induced acute kidney injury. This study also determined the potential mechanism of IRX1 on sepsis-induced inflammatory response and cell apoptosis. Finally, it highlighted that IRX1 exerted a protective influence on CLP-induced acute kidney injury by suppressing the activation of chemokine (C-X-C motif) ligand 14 (CXCL14).

Conclusion: To conclude, the results suggest that overexpression of IRX1 could promote survival rate and suppress the CLP-induced apoptosis, inflammatory response, and kidney dysfunction through the activation of CXCL14. IRX1 and CXCL14 are essential to elucidate the mechanism of acute kidney injury. These findings may help to identify the promising targets for clinical sepsis therapy.

Abstract 162 | PDF Downloads 182 HTML Downloads 8 XML Downloads 2


1. Brent AJ. Sepsis. Medicine. 2017;45(10):649–53. 10.1016/j.mpmed.2017.07.010

2. Fani F, Regolisti G, Delsante M, Cantaluppi V, Castellano G, Gesualdo L, et al. Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury. J Nephrol. 2018;31(3):351–359. 10.1007/s40620-017-0452-4

3. Skube SJ, Katz SA, Chipman JG, Tignanelli CJ. Acute kidney injury and sepsis. Surg Infect. 2018;19(2):216–224. 10.1089/sur.2017.261

4. Ostermann M, McCullough PA, Forni LG, Bagshaw SM, Joannidis M, Shi J, et al. Kinetics of urinary cell cycle arrest markers for acute kidney injury following exposure to potential renal insults. Crit Care Med. 2018;46(3):375. 10.1097/CCM.0000000000002847

5. Shabgah AG, Al-Qaim ZH, Markov A, Yumashev AV, Ezzatifar F, Ahmadi M, et al. Chemokine CXCL14; a double-edged sword in cancer development. Int Immunopharmacol. 2021;97:107681. 10.1016/j.intimp.2021.107681

6. Lu J, Chatterjee M, Schmid H, Beck S, Gawaz M. CXCL14 as an emerging immune and inflammatory modulator. J Inflamm. 2016;13(1):1–8. 10.1186/s12950-015-0109-9

7. Lv J, Wu Z-L, Gan Z, Gui P, Yao S-L. CXCL14 overexpression attenuates sepsis-associated acute kidney injury by inhibiting proinflammatory cytokine production. Mediat Inflamm 2020 Mar 31;2020:2431705. 10.1155/2020/2431705.

8. Øvrevik J, Låg M, Holme J, Schwarze P, Refsnes M. Cytokine and chemokine expression patterns in lung epithelial cells exposed to components characteristic of particulate air pollution. Toxicology. 2009;259(1–2):46–53. 10.1016/j.tox.2009.01.028

9. Kawanishi N, Yano H, Yokogawa Y, Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet--induced obese mice. Exer Immunol Rev. 2010;16:105–18. PMid: 20839495.

10. Bai Y, Sun Q. Macrophage recruitment in obese adipose tissue. Obes Rev. 2015;16(2):127–36. 10.1111/obr.12242

11. Zagozewski JL, Zhang Q, Pinto VI, Wigle JT, Eisenstat DD. The role of homeobox genes in retinal development and disease. Dev Biol. 2014;393(2):195–208. 10.1016/j.ydbio.2014.07.004

12. Bosse A, Stoykova A, Nieselt-Struwe K, Chowdhury K, Copeland NG, Jenkins NA, et al. Identification of a novel mouse Iroquois homeobox gene, Irx5, and chromosomal localisation of all members of the mouse Iroquois gene-family. Dev Dyn. 2000;218(1):160–74. 10.1002/(SICI)1097-0177(200005)218:1<160::AID-DVDY14>3.0.CO;2-2

13. Jung IH, Jung DE, Chung Y-Y, Kim K-S, Park SW. Iroquois homeobox 1 acts as a true tumor suppressor in multiple organs by regulating cell cycle progression. Neoplasia. 2019;21(10):1003–14. 10.1016/j.neo.2019.08.001

14. Yu W, Li X, Eliason S, Romero-Bustillos M, Ries RJ, Cao H, et al. Irx1 regulates dental outer enamel epithelial and lung alveolar type II epithelial differentiation. Dev Biol. 2017;429(1):44–55. 10.1016/j.ydbio.2017.07.011

15. Bhattaram P, Jones K. Regulation of fibroblast-like synoviocyte transformation by transcription factors in arthritic diseases. Biochem Pharmacol. 2019;165:145–51. 10.1016/j.bcp.2019.03.018

16. Zeng L, Gu N, Chen J, Jin G, Zheng Y. IRX1 hypermethylation promotes heart failure by inhibiting CXCL14 expression. Cell Cycle. 2019;18(23):3251–62. 10.1080/15384101.2019.1673099

17. Liu D, Qiao C, Luo H. Micro RNA-1278 ameliorates the inflammation of cardiomyocytes during myocardial ischemia by targeting both IL-22 and CXCL14. Life Sci. 2021;269:118817. 10.1016/j.lfs.2020.118817

18. Wilson RL, Selvaraju V, Lakshmanan R, Thirunavukkarasu M, Campbell J, McFadden DW, et al. Thioredoxin-1 attenuates sepsis-induced cardiomyopathy after cecal ligation and puncture in mice. J Surg Res. 2017;220:68–78. 10.1016/j.jss.2017.06.062

19. Xu D, Chen M, Ren X, Ren X, Wu Y. Leonurine ameliorates LPS-induced acute kidney injury via suppressing ROS-mediated NF-κB signaling pathway. Fitoterapia. 2014;97:148–55. 10.1016/j.fitote.2014.06.005

20. Mei S, Livingston M, Hao J, Mei C, Dong Z. Autophagy is activated to protect against endotoxic acute kidney injury. Sci Rep. 2016;6(1):1–10. 10.1038/srep22171

21. Song C, Adili A, Kari A, Abuduhaer A. FSTL1 aggravates sepsis-induced acute kidney injury through regulating TLR4/MyD88/NF-κB pathway in newborn rats. Signa Vitae. 2021;17(3):167–73. 10.22514/sv.2021.071

22. Li J-L, Li G, Jing X-Z, Li Y-F, Ye Q-Y, Jia H-H, et al. Assessment of clinical sepsis-associated biomarkers in a septic mouse model. J Int Med Res. 2018;46(6):2410–22. 10.1177/0300060518764717

23. Beker BM, Corleto MG, Fieiras C, Musso CG. Novel acute kidney injury biomarkers: Their characteristics, utility and concerns. Int Urol Nephrol. 2018;50(4):705–13. 10.1007/s11255-017-1781-x

24. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380(9843):756–66.10.1016/S0140-6736(11)61454-2

25. Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17(1):1–12. 10.1186/cc12503

26. Hu M-C, Moe OW. Klotho as a potential biomarker and therapy for acute kidney injury. Nature Rev Nephrol. 2012;8(7):423–29. 10.1038/nrneph.2012.92

27. Chaudhry H, Zhou J, Zhong Y, Ali MM, McGuire F, Nagarkatti PS, et al. Role of cytokines as a double-edged sword in sepsis. In Vivo. 2013;27(6):669–84.

28. Nedeva C, Menassa J, Puthalakath H. Sepsis: Inflammation is a necessary evil. Front Cell Dev Biol. 2019;7:108. 10.3389/fcell.2019.00108

29. Xu L, Bao H, Si Y, Wang X. Effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice. Inflamm Res. 2013;62(5):507–14. 10.1007/s00011-013-0604-5

30. Bonegio R, Lieberthal W. Role of apoptosis in the pathogenesis of acute renal failure. Curr Opin Nephrol Hypertens. 2002;11(3):301–8. 10.1097/00041552-200205000-00006

31. Lu J, Song G, Tang Q, Zou C, Han F, Zhao Z, et al. IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling. J Clin Invest. 2015;125(5): 1839–56. 10.1172/JCI78437

32. Frick I-M, Nordin SL, Baumgarten M, Mörgelin M, Sørensen OE, Olin AI, et al. Constitutive and inflammation-dependent antimicrobial peptides produced by epithelium are differentially processed and inactivated by the commensal Finegoldia magna and the pathogen streptococcus pyogenes. J Immunol. 2011;187(8):4300–9. 10.4049/jimmunol.1004179

33. Yang D, Chen Q, Hoover DM, Staley P, Tucker KD, Lubkowski J, et al. Many chemokines including CCL20/MIP-3α display antimicrobial activity. J Leukoc Biol. 2003;74(3):448–55. 10.1189/jlb.0103024