Radiation-induced intestinal injury (RIII) significantly impairs the quality of life in patients with abdominal/pelvic cancer undergoing radiotherapy, often necessitating treatment cessation. The ACE2/Ang-(1–7)/MasR axis, a protective pathway within the renin-angiotensin system, represents a potential anti-inflammatory target. This study explored the role of ACE2 activation in mitigating RIII and the underlying mechanisms.
Results:
Treatment with diminazene aceturate (DIZE), a selective ACE2 agonist, prior to lethal radiation blocked intestinal stem cell (ISC) death, enhanced crypt regeneration, preserved epithelial barrier integrity, and reduced intestinal inflammation, thereby promoting mice survival. Notably, the radioprotective effect of DIZE was reversed by ACE2 or MasR antagonists, and other ACE2 agonists exhibited similar radioprotective efficacy. DIZE treatment improved the survival of ISCs both in vitro and in vivo postradiation. Mechanistically, DIZE directly targeted intestinal epithelial cells (IECs), preventing the activation of radiation-induced MAPK (p38/JNK) and NF-κB pathways. This effect was abolished by ACE2 knockdown in a human intestinal epithelial cell line (HIECs) in vitro. Intriguingly, DIZE failed to inhibit endothelial cell apoptosis or attenuate MAPK/NF-κB pathway activation in irradiated endothelial cells. Preliminary evidence indicates DIZE did not affect the radiosensitivity of colorectal tumor cells or azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal tumors in mice.
Conclusion and Innovation:
This study is the first to demonstrate selective ACE2-mediated intestinal protection without compromising tumor radiosensitivity. These findings demonstrate ACE2 activation selectively shields IECs from radiation damage by inhibiting MAPK/NF-κB pathways, offering a novel therapeutic strategy to alleviate RIII without compromising tumor radiosensitivity. Antioxid. Redox Signal. 44, 843–858.
BracciS, ValerianiM, AgolliL, et al.Renin-angiotensin system inhibitors might help to reduce the development of symptomatic radiation pneumonitis after stereotactic body radiotherapy for lung cancer. Clin Lung Cancer, 2016; 17(3):189–197; doi: 10.1016/j.cllc.2015.08.007
4.
DongF, LiH, LiuL, et al.ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity. Int J Biol Sci, 2023; 19(8):2613–2629; doi: 10.7150/ijbs.81498
5.
DouillardM, DehebZ, BozonA, et al.Over diagnosis of bradykinin angioedema in patients treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. World Allergy Organ J, 2023; 16(8):100809; doi: 10.1016/j.waojou.2023.100809
6.
FanJ, LinB, FanM, et al.Research progress on the mechanism of radiation enteritis. Front Oncol, 2022; 12:888962; doi: 10.3389/fonc.2022.888962
7.
FändriksL. The renin-angiotensin system and the gastrointestinal mucosa. Acta Physiol (Oxf), 2011; 201(1):157–167; doi: 10.1111/j.1748-1716.2010.02165.x
8.
GasperettiT, SharmaGP, FreiAC, et al.Mitigation of multi-organ radiation injury with ACE2 agonist diminazene aceturate. Radiat Res, 2022; 198(4):325–335; doi: 10.1667/rade-22-00055.1
9.
GoiteinM. How best to dispose of extra-tumoral dose: A cautionary note for intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys, 2009; 75(1):1–3; doi: 10.1016/j.ijrobp.2009.05.053
KefaloyianniE, GaitanakiC, BeisI. ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-kappaB transactivation during oxidative stress in skeletal myoblasts. Cell Signal, 2006; 18(12):2238–2251; doi: 10.1016/j.cellsig.2006.05.004
15.
KhannaP, SohHJ, ChenCH, et al.ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1–7) as a therapy for clear cell renal cell carcinoma. Sci Transl Med, 2021; 13(577):eabc0170; doi: 10.1126/scitranslmed.abc0170
16.
KimD, JeongW, KimY, et al.Pharmacologic activation of angiotensin-converting enzyme II alleviates diabetic cardiomyopathy in db/db mice by reducing reactive oxidative stress. Diabetes Metab J, 2023; 47(4):487–499; doi: 10.4093/dmj.2022.0125
17.
LamersMM, BeumerJ, van der VaartJ, et al.SARS-CoV-2 productively infects human gut enterocytes. Science, 2020; 369(6499):50–54; doi: 10.1126/science.abc1669
18.
LeonettiD, EstéphanH, RipocheN, et al.Secretion of acid sphingomyelinase and ceramide by endothelial cells contributes to radiation-induced intestinal toxicity. Cancer Res, 2020; 80(12):2651–2662; doi: 10.1158/0008-5472.Can-19-1527
19.
LiJ, YanY, FuY, et al.ACE2 mediates tryptophan alleviation on diarrhea by repairing intestine barrier involved mTOR pathway. Cell Mol Biol Lett, 2024a;29(1):90; doi: 10.1186/s11658-024-00603-8
20.
LiJX, XiaoX, TengF, et al.Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1–7)-Mas-mediated macrophage polarization. Redox Biol, 2024b;69:103004; doi: 10.1016/j.redox.2023.103004
21.
LivanovaAA, FedorovaAA, ZavirskyAV, et al.Dose- and segment-dependent disturbance of rat gut by ionizing radiation: Impact of tight junction proteins. Int J Mol Sci, 2023; 24(2):1753; doi: 10.3390/ijms24021753
22.
MooreED, KooshkiM, Metheny-BarlowLJ, et al.Angiotensin-(1-7) prevents radiation-induced inflammation in rat primary astrocytes through regulation of MAP kinase signaling. Free Radic Biol Med, 2013; 65:1060–1068; doi: 10.1016/j.freeradbiomed.2013.08.183
23.
NageshPKB, MonetteS, ShamuT, et al.Anti-ceramide single-chain variable fragment mitigates gastrointestinal-acute radiation syndrome and improves marrow reconstitution, rendering near-normal 90-day autopsies. Int J Radiat Oncol Biol Phys, 2024; 120(2):558–569; doi: 10.1016/j.ijrobp.2023.07.038
24.
NussinovR, JangH, ChengF. Ras, RhoA, and vascular pharmacology in neurodevelopment and aging. Neurochem Int, 2024; 181:105883; doi: 10.1016/j.neuint.2024.105883
25.
OzturkT, MignotJ, GattazzoF, et al.Dual inhibition of P38 MAPK and JNK pathways preserves stemness markers and alleviates premature activation of muscle stem cells during isolation. Stem Cell Res Ther, 2024; 15(1):179; doi: 10.1186/s13287-024-03795-0
26.
ParisF, FuksZ, KangA, et al.Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science, 2001; 293(5528):293–297; doi: 10.1126/science.1060191
27.
PeregrineAS, MammanM. Pharmacology of diminazene: A review. Acta Trop, 1993; 54(3–4):185–203; doi: 10.1016/0001-706x(93)90092-p
28.
PotdarAA, DubeS, NaitoT, et al.Altered intestinal ACE2 levels are associated with inflammation, severe disease, and response to anti-cytokine therapy in inflammatory bowel disease. Gastroenterology, 2021; 160(3):809–822.e807; doi: 10.1053/j.gastro.2020.10.041
29.
RaoA, BhatSA, ShibataT, et al.Diverse biological functions of the renin-angiotensin system. Med Res Rev, 2024; 44(2):587–605; doi: 10.1002/med.21996
30.
SaavedraJM. Beneficial effects of angiotensin II receptor blockers in brain disorders. Pharmacol Res, 2017; 125(Pt A):91–103; doi: 10.1016/j.phrs.2017.06.017
31.
SharmaGP, FishBL, FreiAC, et al.Pharmacologic ACE-inhibition mitigates radiation-induced pneumonitis by suppressing ACE-expressing lung myeloid cells. Int J Radiat Oncol Biol Phys, 2022; 113(1):177–191; doi: 10.1016/j.ijrobp.2022.01.023
32.
SharmaGP, FreiA, FishB, et al.Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury. Front Physiol, 2023; 14:1191237; doi: 10.3389/fphys.2023.1191237
33.
Simões e SilvaAC, SilveiraKD, FerreiraAJ, et al.ACE2, angiotensin-(1–7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol, 2013; 169(3):477–492; doi: 10.1111/bph.12159
34.
TaoL, QiuY, FuX, et al.Angiotensin-converting enzyme 2 activator diminazene aceturate prevents lipopolysaccharide-induced inflammation by inhibiting MAPK and NF-κB pathways in human retinal pigment epithelium. J Neuroinflammation, 2016; 13:35; doi: 10.1186/s12974-016-0489-7
35.
van der FlierLG, HaegebarthA, StangeDE, et al.OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology, 2009; 137(1):15–17; doi: 10.1053/j.gastro.2009.05.035
36.
VenkatesuluBP, MahadevanLS, AliruML, et al.Radiation-induced endothelial vascular injury. JACC: Basic to Translational Science, 2018; 3(4):563–572; doi: 10.1016/j.jacbts.2018.01.014
37.
WangS, WuX, BiW, et al.ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3. Nat Commun, 2025; 16(1):1406; doi: 10.1038/s41467-025-56444-2
38.
WeiL, BoL, LuoC, et al.Transplantation of human umbilical cord-derived mesenchymal stem cells improves age-related ovarian functional decline via regulating the local renin-angiotensin system on inflammation and oxidative stress. Stem Cell Res Ther, 2024; 15(1):377; doi: 10.1186/s13287-024-03997-6
39.
WijerathneH, LangstonJC, YangQ, et al.Mechanisms of radiation-induced endothelium damage: Emerging models and technologies. Radiother Oncol, 2021; 158:21–32; doi: 10.1016/j.radonc.2021.02.007
40.
XiaoX, LiJX, LiHH, et al.ACE2 alleviates sepsis-induced cardiomyopathy through inhibiting M1 macrophage via NF-κB/STAT1 signals. Cell Biol Toxicol, 2024; 40(1):82; doi: 10.1007/s10565-024-09923-z
41.
XieP, GuoL, YuQ, et al.ACE2 enhances sensitivity to PD-L1 blockade by inhibiting macrophage-induced immunosuppression and angiogenesis. Cancer Res, 2025; 85(2):299–313; doi: 10.1158/0008-5472.Can-24-0954
42.
YangXF, ZhengMY, AnLY, et al.Quality evaluation of guidelines for the diagnosis and treatment of radiation enteritis. Radiat Oncol, 2023; 18(1):14; doi: 10.1186/s13014-023-02204-9
43.
YisireyiliM, UchidaY, YamamotoK, et al.Angiotensin receptor blocker Irbesartan reduces stress-induced intestinal inflammation via AT1a signaling and ACE2-dependent mechanism in mice. Brain Behav Immun, 2018; 69:167–179; doi: 10.1016/j.bbi.2017.11.010
44.
YuX, CuiL, HouF, et al.Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway. Int J Mol Med, 2018; 41(1):409–420; doi: 10.3892/ijmm.2017.3252
45.
ZhangC, CaoX, WangH, et al.The ACE2 activator diminazene aceturate ameliorates colitis by repairing the gut-vascular barrier in mice. Microvasc Res, 2023; 148:104544; doi: 10.1016/j.mvr.2023.104544
46.
ZhangQQ, ChenFH, WangF, et al.A novel modulator of the renin-angiotensin system, benzoylaconitine, attenuates hypertension by targeting ACE/ACE2 in enhancing vasodilation and alleviating vascular inflammation. Front Pharmacol, 2022; 13:841435; doi: 10.3389/fphar.2022.841435
47.
ZhangW, JiaoB, YuS, et al.Spinal AT1R contributes to neuroinflammation and neuropathic pain via NOX2-dependent redox signaling in microglia. Free Radic Biol Med, 2025; 227:143–156; doi: 10.1016/j.freeradbiomed.2024.12.004
48.
ZhangYH, ZhangYH, DongXF, et al.ACE2 and Ang-(1–7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response. Inflamm Res, 2015; 64(3–4):253–260; doi: 10.1007/s00011-015-0805-1
49.
ZhouJ, LiC, LiuX, et al.Infection of bat and human intestinal organoids by SARS-CoV-2. Nat Med, 2020; 26(7):1077–1083; doi: 10.1038/s41591-020-0912-6
50.
ZhuP, ZhangW, FengF, et al.Role of angiotensin-converting enzyme 2 in fine particulate matter-induced acute lung injury. Sci Total Environ, 2022; 825:153964; doi: 10.1016/j.scitotenv.2022.153964
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
