Exosomes Secreted by ATF3/Nrf2-mediated Ferroptotic Renal Tubular Epithelial Cells Promote M1/M2 Ratio Imbalance Inducing Renal Interstitial Fibrosis Following Ischemia and Reperfusion Injury

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2025 Feb 20

PMID 39975560

Authors

Qiao Tang

Jiatao Xie

Yifei Wang

Chong Dong

Qian Sun

Affiliations

Soon will be listed here.

Abstract

Background: Severe renal ischemia and reperfusion injury (IRI) progresses to renal interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis and macrophage polarization both play important roles in this model, their specific pathogenesis and interactions have not been elucidated. Therefore, we aimed to explore the mechanisms by which ferrotosis occurs in renal tubular epithelial cells (RTECs) and ferroptotic cell-derived exosomes induce macrophage polarization in IRI-related RIF model.

Methods: , C57BL/6J mice were randomly divided into four groups: sham group, ischemia and reperfusion (IR) group, IR + Ferrostatin-1 (Fer-1) group, and IR +ATF3 knockdown (ATF) group. , RTECs were divided into control (CON) group, hypoxia/reoxygenation (HR) group, HR +Fer-1 group, HR + siRNA-ATF3 (siATF3) group.

Result: Compared with the sham group, the IR group showed more severe kidney injury in HE staining, more collagen fibers in Masson staining, and higher α-SMA expression levels in immunohistochemistry. Total iron and MDA content increased while GSH content decreased. The IR group had more significant mitochondrial damage and higher PTGS2 and TFRC mRNA levels than those in the sham group. Compared with the IR group, the above indexes were all alleviated in the IR+Fer-1 or IR+ATF3 groups. In addition, the protein expressions of ATF3, Nrf2 and HO-1 in the IR group were increased than those in sham group. Compared with the IR group, ATF3 expressions in the IR+Fer-1 or IR+ATF3 groups were decreased, and the protein contents of Nrf2 and HO-1 were further increased. Moreover, there were higher levels of M2 markers (Arg1, TGF-β and IL-10 mRNA) in the IR group than those in the sham group, and lower levels in the IR+Fer-1 group or in the IR+ATF3 group compared with the IR group. The results of experiment are consistent with those of experiment. Mechanistically, the release of exosomes carrying miR-1306-5p by the HR group promoted more M2 macrophage.

Conclusion: ATF3 might accelerate the ferroptosis by inhibiting Nrf2/ARE pathway, and exosomes from ferroptotic cells reduced the M1/M2 macrophage ratio, promoting fibrosis.

References

Tang Q, Li J, Wang Y, Sun Q . Identification and verification of hub genes associated with ferroptosis in ischemia and reperfusion injury during renal transplantation. Int Immunopharmacol. 2023; 120:110393. DOI: 10.1016/j.intimp.2023.110393. View

Kurzhagen J, Dellepiane S, Cantaluppi V, Rabb H . AKI: an increasingly recognized risk factor for CKD development and progression. J Nephrol. 2020; 33(6):1171-1187. DOI: 10.1007/s40620-020-00793-2. View

Gong S, Zhang A, Yao M, Xin W, Guan X, Qin S . REST contributes to AKI-to-CKD transition through inducing ferroptosis in renal tubular epithelial cells. JCI Insight. 2023; 8(11). PMC: 10393228. DOI: 10.1172/jci.insight.166001. View

G Hindle A, Thoonen R, Jasien J, Grange R, Amin K, Wise J . Identification of Candidate miRNA Biomarkers for Glaucoma. Invest Ophthalmol Vis Sci. 2019; 60(1):134-146. PMC: 6329203. DOI: 10.1167/iovs.18-24878. View

Li Z, Lv L, Tang T, Wang B, Feng Y, Zhou L . HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation. Kidney Int. 2018; 95(2):388-404. DOI: 10.1016/j.kint.2018.09.013. View

Wang Y, Quan F, Cao Q, Lin Y, Yue C, Bi R . Quercetin alleviates acute kidney injury by inhibiting ferroptosis. J Adv Res. 2020; 28:231-243. PMC: 7753233. DOI: 10.1016/j.jare.2020.07.007. View

Maremonti F, Meyer C, Linkermann A . Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss. J Am Soc Nephrol. 2022; 33(3):472-486. PMC: 8975069. DOI: 10.1681/ASN.2021101293. View

Fu Y, Xiang Y, Li H, Chen A, Dong Z . Inflammation in kidney repair: Mechanism and therapeutic potential. Pharmacol Ther. 2022; 237:108240. DOI: 10.1016/j.pharmthera.2022.108240. View

Bosco M . Macrophage polarization: Reaching across the aisle?. J Allergy Clin Immunol. 2019; 143(4):1348-1350. DOI: 10.1016/j.jaci.2018.12.995. View

10.

Linkermann A, Skouta R, Himmerkus N, Mulay S, Dewitz C, De Zen F . Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014; 111(47):16836-41. PMC: 4250130. DOI: 10.1073/pnas.1415518111. View

11.

Zhao H, Alam A, Pac Soo A, George A, Ma D . Ischemia-Reperfusion Injury Reduces Long Term Renal Graft Survival: Mechanism and Beyond. EBioMedicine. 2018; 28:31-42. PMC: 5835570. DOI: 10.1016/j.ebiom.2018.01.025. View

12.

Ponticelli C, Campise M . The inflammatory state is a risk factor for cardiovascular disease and graft fibrosis in kidney transplantation. Kidney Int. 2021; 100(3):536-545. DOI: 10.1016/j.kint.2021.04.016. View

13.

Yoshida T, Sugiura H, Mitobe M, Tsuchiya K, Shirota S, Nishimura S . ATF3 protects against renal ischemia-reperfusion injury. J Am Soc Nephrol. 2008; 19(2):217-24. PMC: 2396738. DOI: 10.1681/ASN.2005111155. View

14.

Zhao S, Li W, Yu W, Rao T, Li H, Ruan Y . Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys. Theranostics. 2021; 11(18):8660-8673. PMC: 8419054. DOI: 10.7150/thno.62820. View

15.

Balzer M, Doke T, Yang Y, Aldridge D, Hu H, Mai H . Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration. Nat Commun. 2022; 13(1):4018. PMC: 9276703. DOI: 10.1038/s41467-022-31772-9. View

16.

Zhang B, Chen X, Ru F, Gan Y, Li B, Xia W . Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis. Cell Death Dis. 2021; 12(9):843. PMC: 8435531. DOI: 10.1038/s41419-021-04137-1. View

17.

Poyan Mehr A, Tran M, Ralto K, Leaf D, Washco V, Messmer J . De novo NAD biosynthetic impairment in acute kidney injury in humans. Nat Med. 2018; 24(9):1351-1359. PMC: 6129212. DOI: 10.1038/s41591-018-0138-z. View

18.

Chen X, Kang R, Kroemer G, Tang D . Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021; 218(6). PMC: 8126980. DOI: 10.1084/jem.20210518. View

19.

Zhou Y, Zhang J, Guan Q, Tao X, Wang J, Li W . The role of ferroptosis in the development of acute and chronic kidney diseases. J Cell Physiol. 2022; 237(12):4412-4427. DOI: 10.1002/jcp.30901. View

20.

Sun S, Wu Y, Maimaitijiang A, Huang Q, Chen Q . Ferroptotic cardiomyocyte-derived exosomes promote cardiac macrophage M1 polarization during myocardial infarction. PeerJ. 2022; 10:e13717. PMC: 9270880. DOI: 10.7717/peerj.13717. View