Lumbar disc herniation (LDH) involves inflammation and metabolic stress. Tissue-specific renin-angiotensin-aldosterone system (RAAS) signaling may act as an upstream regulator of disc degeneration. This study investigates RAAS dysregulation as a central driver of LDH and its contribution to inflammation, metabolic reprogramming, and disc injury.
Methods
Bulk and single-cell transcriptomics assessed RAAS activity, while MR/GWAS analyses examined causality. Machine learning with the MIMIC database identified biomarkers. In vitro nucleus pulposus cell experiments validated the ACE2/Ang(1–7)/MAS1 protective axis.
Results
RAAS components ACE, AGTR1, ACE2, AGTR2, and MAS1 were dysregulated in LDH across disc cells, immune populations, and endothelium, with a shift toward glycolysis. Patients showed elevated Ang II/Ang(1–7) ratios. Ang II induced NF-κB mediated inflammation, extracellular matrix degradation, and apoptosis, reversible by losartan or protective axis activation.
Conclusion
RAAS dysregulation serves as an upstream hub driving inflammation, metabolic imbalance, extracellular matrix breakdown, and disc cell injury in LDH. Therapeutic strategies should suppress the ACE/Ang II/AT1 axis while enhancing the ACE2/Ang(1–7)/MAS1 protective pathway.
Integrated multi-omics analyses identify renin–angiotensin system dysregulation as a key driver of lumbar disc herniation. Classical ACE/Ang II signaling promotes inflammation and matrix degradation, whereas the ACE2/Ang-(1–7)/MAS1 axis counteracts degenerative processes.
BeallDPKimKDMacadaegK, et al.Treatment gaps and emerging therapies in lumbar disc herniation. PPJ2024; 27: 401–413.
2.
González-JohnsonLRojas-SoleCHermosilla-AstudilloF, et al.Lumbar disc herniation and radiculopathy: an integrative neurological review of pathophysiology, diagnosis, and evolving management paradigms. AN2026; 0: 025440108. doi: 10.36922/AN025440108
3.
YuBZhengJ. Treatment of lumbar intervertebral disc herniation using open spinal endoscopy: techniques and clinical outcomes. Medicine Advances2024; 2: 186–194.
4.
MengZ. The relationship between biomechanical factors and intervertebral disc degeneration: a review. Am J Transl Res2025; 17: 3575–3585.
5.
CazzanelliPWuertz-KozakK. MicroRNAs in intervertebral disc degeneration, apoptosis, inflammation, and mechanobiology. IJMS2020; 21: 3601.
6.
ZąbekZWyczałkowska-TomasikAPobożyK, et al.Understanding the microenvironment of intervertebral disc degeneration: a comprehensive review of pathophysiological insights and therapeutic implications. IJMS2025; 26: 9938.
7.
MaiYWuSZhangP, et al.The anti-oxidation related bioactive materials for intervertebral disc degeneration regeneration and repair. Bioactive Mater2025; 45: 19–40.
8.
Cosamalón-GanICosamalón-GanTMattos-PiaggioG, et al.Inflamación en la hernia del disco intervertebral. Neurocirugía2021; 32: 21–35.
9.
GongGYanZLaiQ, et al.Inflammation preservation strategy: reconciling pain control and disc resorption in lumbar disc herniation. Front Immunol2025; 16: 1653681.
10.
OhnishiTNovaisEJRisbudMV. Alterations in ECM signature underscore multiple sub-phenotypes of intervertebral disc degeneration. Matrix Biol Plus2020; 6–7: 100036.
11.
Spine Research Group, Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Winterthurerstrasse 190 (17L28), 8057 Zurich, Switzerland; WuertzKVoNKletsasD,et al.Inflammatory and catabolic signalling in intervertebral discs: the roles of NF-kB and MAP kinases. eCM2012; 23: 102–120.
12.
ZhouHHeJLiuR, et al.Microenvironment-responsive metal-phenolic network release platform with ROS scavenging, anti-pyroptosis, and ECM regeneration for intervertebral disc degeneration. Bioactive Mater2024; 37: 51–71.
13.
PengZWangZGuoS, et al.An analysis of the transcriptional landscape in hypoxia-treated primary nucleus pulposus cells. Genes Dis2024; 11: 558–560.
14.
ZhouLCaiFZhuH, et al.Immune-defensive microspheres promote regeneration of the nucleus pulposus by targeted entrapment of the inflammatory cascade during intervertebral disc degeneration. Bioactive Mater2024; 37: 132–152.
15.
KritschilRScottMSowaG,et al.Role of autophagy in intervertebral disc degeneration. J Cell Physiol2022; 237: 1266–1284.
16.
RisbudMVSchipaniEShapiroIM. Hypoxic regulation of nucleus Pulposus cell survival. Am J Pathol2010; 176: 1577–1583.
17.
ZhuDLiangHDuZ, et al.Altered metabolism and inflammation driven by post-translational modifications in intervertebral disc degeneration. Research2024; 7: 0350.
18.
RaoABhatSAShibataT, et al.Diverse biological functions of the renin-angiotensin system. Med Res Rev2024; 44: 587–605.
19.
Nguyen DinhCATouyzRM. A new look at the renin–angiotensin system—focusing on the vascular system. Peptides2011; 32: 2141–2150.
20.
GuffroyBMiguetLLioureB, et al.Renin-Angiotensin system drives leukemia progression by reprogramming the niche. Discov Med2025; 37: 09.
21.
SaraviBLiZLangCN, et al.The tissue renin-angiotensin system and its role in the pathogenesis of major human diseases: quo vadis?Cells2021; 10: 650.
22.
NehmeAZoueinFADeris ZayeriZ,et al.An update on the tissue renin angiotensin system and its role in physiology and pathology. JCDD2019; 6: 14.
23.
AfzalSSattarMAAlbokhadaimI, et al.Interaction between nuclear receptor and alpha-adrenergic agonist subtypes in metabolism and systemic hemodynamics of spontaneously hypertensive rats. PPAR Res2024; 2024: 5868010.
24.
CaputoIBertoldiGDriussiG, et al.The RAAS goodfellas in cardiovascular system. JCM2023; 12: 6873.
25.
Rodrigues PrestesTRRochaNPMirandaAS, et al.The anti-inflammatory potential of ACE2/Angiotensin-(1-7)/Mas receptor axis: Evidence from basic and clinical research. CDT2017; 18. doi: 10.2174/1389450117666160727142401
26.
LuoZWeiZZhangG, et al.Achilles’ heel—the significance of maintaining microenvironmental homeostasis in the nucleus pulposus for intervertebral discs. IJMS2023; 24: 16592.
27.
ShnayderNAAshhotovAVTrefilovaVV, et al.Cytokine imbalance as a biomarker of intervertebral disk degeneration. IJMS2023; 24: 2360.
28.
De Barcelos Ubaldo MartinsLJabourLGPPVieiraCC, et al.Renin angiotensin system (RAS) and immune system profile in specific subgroups with COVID-19. Curr Med Chem2021; 28: 4499–4530.
29.
XiangHZhaoWJiangK, et al.Progress in regulating inflammatory biomaterials for intervertebral disc regeneration. Bioactive Mater2024; 33: 506–531.
30.
WangYDaiGJiangL, et al.Microarray analysis reveals an inflammatory transcriptomic signature in peripheral blood for sciatica. BMC Neurol2021; 21: 50.
31.
WangYDaiGLiL, et al.Transcriptome signatures reveal candidate key genes in the whole blood of patients with lumbar disc prolapse. Exp Ther Med2019; 18: 4591–4602.
32.
SunCMaSChenY, et al.Diagnostic value, prognostic value, and immune infiltration of LOX family members in liver cancer: bioinformatic analysis. Front Oncol2022; 12: 843880.
33.
MaFWangLChiH, et al.Exploring the therapeutic potential of MIR -140-3p in osteoarthritis: targeting CILP and ferroptosis for novel treatment strategies. Cell Prolif2025; 58: e70018.
34.
JiaSLiuHYangT, et al.Single-cell sequencing reveals cellular heterogeneity of nucleus pulposus in intervertebral disc degeneration. Sci Rep2024; 14: 27245.
35.
YangGDongCWuZ, et al.Single-cell RNA sequencing-guided engineering of mitochondrial therapies for intervertebral disc degeneration by regulating mtDNA/SPARC-STING signaling. Bioactive Materials2025; 48: 564–582.
36.
ZhangLCuiYMeiJ, et al.Exploring cellular diversity in lung adenocarcinoma epithelium: advancing prognostic methods and immunotherapeutic strategies. Cell Prolif2024; 57: e13703.
37.
ChenYGuoLShenJ, et al.ACE2/ang(1–7)/MasR Axis exerts protective effects on lung ischemia/reperfusion injury via NF-κB-dependent mitochondrial adaptation and epithelial cell pyroptosis. Int Immunopharmacol2025; 164: 115325.
38.
WangLHeTLiuJ, et al.Revealing the immune infiltration landscape and identifying diagnostic biomarkers for lumbar disc herniation. Front Immunol2021; 12: 666355.
39.
CunhaCSilvaAJPereiraP, et al.The inflammatory response in the regression of lumbar disc herniation. Arthritis Res Ther2018; 20: 251.
40.
BydonMMoinuddinFYolcuYU, et al.Lumbar intervertebral disc mRNA sequencing identifies the regulatory pathway in patients with disc herniation and spondylolisthesis. Gene2020; 750: 144634.
41.
HuangGShenHXuK, et al.Single-Cell microgel encapsulation improves the therapeutic efficacy of mesenchymal stem cells in treating intervertebral disc degeneration via inhibiting pyroptosis. Research2024; 7: 0311.
42.
SunKSunXSunJ, et al.Tissue renin-angiotensin system (tRAS) induce intervertebral disc degeneration by activating oxidative stress and inflammatory reaction. Oxid Med Cell Longevity2021; 2021: 3225439.
43.
LiuQChenQZhuangX, et al.Comprehensive analysis of molecular pathways and key genes involved in lumbar disc herniation. Medicine (Baltimore)2021; 100: e25093.
44.
WangHLiuWYuB, et al.Identification of key modules and hub genes of annulus fibrosus in intervertebral disc degeneration. Front Genet2021; 11: 596174.
45.
SaraviBLiZBasoliV, et al.In vitro characterization of a tissue renin-angiotensin system in human nucleus pulposus cells. Cells2022; 11: 3418.
46.
ShaoTGaoQTangW, et al.The role of immunocyte infiltration regulatory network based on hdWGCNA and single-cell bioinformatics analysis in intervertebral disc degeneration. Inflammation2024; 47: 1987–1999.
47.
BalakumarPOrayjKMKhanNA, et al.Impact of the local renin–angiotensin system in perivascular adipose tissue on vascular health and disease. Cell Signalling2024; 124: 111461.
48.
YangLLiJCuiZ, et al.Integrating bulk RNA and single-cell sequencing data reveals genes related to energy metabolism and efferocytosis in lumbar disc herniation. Biomedicines2025; 13: 1536.
49.
WangWLiuLMaW, et al.An anti-senescence hydrogel with pH-responsive drug release for mitigating intervertebral disc degeneration and low back pain. Bioactive Mater2024; 41: 355–370.
50.
ShanLYangJMengS, et al.Urine metabolomics profiling of lumbar disc herniation and its traditional Chinese medicine subtypes in patients through gas chromatography coupled with mass spectrometry. Front Mol Biosci2021; 8: 648823.
51.
ParkYKangDSinnDH, et al.Effect of renin-angiotensin system inhibitor in incident cancer among chronic hepatitis B patients: an emulated target trial using a nationwide cohort. J Renin Angiotensin Aldosterone Syst2024; 25: 14703203241294037.
52.
CuiYChenFGaoJ, et al.Comprehensive landscape of the renin-angiotensin system in pan-cancer: a potential downstream mediated mechanism of SARS-CoV-2. Int J Biol Sci2021; 17: 3795–3817.
53.
ZhaoYChenLJiangS, et al.Exosomes derived from MSCs exposed to hypoxic and inflammatory environments slow intervertebral disc degeneration by alleviating the senescence of nucleus pulposus cells through epigenetic modifications. Bioactive Mater2025; 49: 515–530.
54.
Department of Orthopaedics and Trauma Surgery, Medical Centre, Faculty of Medicine, Albert Ludwig University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany; LiZWystrachLBernsteinA, et al.The tissue-renin-angiotensin-system of the human intervertebral disc. Eur Cells Mater2020; 40: 115–132.
55.
XieBGuYLiJ, et al.Angiotensin II and AGTR1 in ESCC proliferation and invasion: insights from the JAK/STAT3 pathway. Discov Med2025; 37: 394.
56.
SaraviBLiZPfannkucheJ, et al.Angiotensin II type 1 receptor antagonist losartan inhibits TNF-α-induced inflammation and degeneration processes in human nucleus pulposus cells. Appl Sci2021; 11: 17.
57.
ZhongyiSSaiZChaoL,et al.Effects of nuclear factor kappa B signaling pathway in human intervertebral disc degeneration. Spine2015; 40: 224–232.
58.
AbuohashishHMAhmedMMSabryD, et al.The ACE-2/Ang1-7/mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade. Eur J Pharmacol2017; 807: 44–55.
59.
Rukavina MikusicNLPinedaAMGironacciMM. Angiotensin-(1-7) and mas receptor in the brain. Explor Med2021; 2: 268–293.
60.
NishidaTAkashiSTakigawaM,et al.Effect of angiotensin II on chondrocyte degeneration and protection via differential usage of angiotensin II receptors. IJMS2021; 22: 9204.
61.
ValentiniAHeilmannRMKühneA, et al.The renin–angiotensin–aldosterone system (RAAS): beyond cardiovascular regulation. Veterinary Sci2025; 12: 777.
62.
TomarPSYadavSBukkeSPN, et al.Molecular pathways for targeted therapeutics in the management of COVID-19 and heart failure. J Renin Angiotensin Aldosterone Syst2025; 26: 14703203251351110.
63.
TranAVNguyenAPTranPT, et al.The prognostic value of AGTR1 A1166C gene polymorphism in all-cause mortality and heart failure in patients with acute myocardial infarction. J Renin Angiotensin Aldosterone Syst2025; 26: 14703203241312627.
64.
LiZTangYWangL, et al.Tetrahedral framework nucleic acids-based delivery of microRNA -155 alleviates intervertebral disc degeneration through targeting Bcl-2/Bax apoptosis pathway. Cell Prolif2024; 57: e13689.
65.
LiuHLiYKarsidagM, et al.Technical and biological biases in bulk transcriptomic data mining for cancer research. J Cancer2025; 16: 34–43.
66.
LiuJLiuCXiaoH,et al.Understanding vascular toxicity of Indigo naturalis in anti-inflammatory applications: Mendelian randomization and co-localization study. BIOI2025; 6. doi: 10.15212/bioi-2025-0155
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