Gerik Grabowski

Background: Acute Kidney Injury (AKI) is a multifactorial condition resulting from impaired kidney function which can ultimately impact multiple organ systems including the cardiovascular, GI, and pulmonary systems.^1,2 AKI is a widely prevalent condition affecting 10-15% of hospitalized patients globally.¹ Trauma results in AKI through the upregulation of renal damage markers, physiological damage to renal structures, and renal ischemia.³ Trauma related acute kidney injury (TRAKI) leads to a 3X increase in mortality rate, and is present in 24% of severe trauma patients, therefore, understanding the molecular mechanisms of injury propagation could lead to a significant clinical impact.^1,3,4 Damage-Associated Molecular Patterns (DAMPs) are endogenous molecules released by damaged cells and propagate inflammation in AKI.^2,3 One specific DAMP elevated in TRAKI is High Mobility Group Box 1 (HMGB1).^3,4 While past studies have shown HMGB1’s exacerbating effects on AKI, alternative studies have demonstrated that coupling HMGB1 with secondary signaling molecules, C1q and the receptor for advanced glycation end product (RAGE), promotes anti-inflammatory immune modulations and lymphangiogenesis.^5,6,7

Objective: In this narrative review, we explored mechanisms in which HMGB1’s pro-inflammatory effects might be modulated by secondary signaling molecules to improve TRAKI through lymphangiogenesis.

Search Methods: An online search using PubMed, Google Scholar, and ChatGPT was conducted from 2019 to 2026 using the keywords “acute kidney injury”, “trauma”, “HMGB1”, “RAGE”, “lymphangiogenesis”.

Results: Studies indicate that decreasing the mean arterial pressure by 30 mmHg for 60 minutes in mice significantly increased plasma creatinine and urea, indicating AKI.³ Studied generated an HMGB1 KO mouse to evaluate HMGB1’s effect on the prognosis and development of AKI.^3,4,5 HMGB1 KO mice demonstrated improved GFR and less renal tubular cell death post ischemic reperfusion induced AKI, indicating that HMGB1 exacerbates AKI.⁵ However, when HMGB1 was added along with C1q, a modulator of monocyte mediated inflammation and repair, mice suffering from AKI saw a decrease in the proinflammatory molecules LTB4 and TNF-alpha, and an increase in the anti-inflammatory molecules TGF-beta and RSV2, a specialized proresolving mediator (SPM).⁶ This work demonstrated that the immune effects of HMGB1 are dependent on a number of signaling pathway molecules including C1q, RAGE, interferon regulatory factor 5 (IRF5), leukocyte-associated immunoglobulin like receptor 1 (LAIR-1), and SH2 domain-containing protein tyrosine phosphatase-1 (SHP-1).⁶ The HMGB1-RAGE complex stimulates IRF5 to increase transcription of LTB4, promoting inflammation.⁶ However, when the HMGB1-RAGE complex is coupled with C1q, LAIR-1, and SHP-1, an SPM driven anti-inflammatory response is invoked.⁶ Furthermore, the HMGB1-RAGE complex increased the migration and synthesis of human dermal lymphatic endothelial cells (HDLECs) in vivo.⁷ An improvement in kidney function and a decrease in tubular fibrosis post AKI was shown when lymphangiogenesis was upregulated via a VEGF-D overexpressing mouse model.⁸

Conclusion: Studies have indicated an increase in anti-inflammatory molecules and a decrease in proinflammatory molecules when HMGB1 is coupled with RAGE, C1q, LAIR-1, and SHP-1. Likewise, the HMGB1-RAGE complex stimulates an increase in migration and proliferation of HDLECs, promoting lymphangiogenesis. This combination of an increase in anti-inflammatory cytokines and lymphangiogensis could serve as a target to improve prognosis in patients suffering from AKI.

Works Cited:

1. Xu X, Zeng T, Chen S, et al. Acute kidney injury: pathogenesis and therapeutic interventions.Mol Biomed. 2025;6(1):61. Published 2025 Sep 5. doi:10.1186/s43556-025-00293-4
2. Li J, Hu Z. Research progress on damage-associated molecular patterns in acute kidney injury.Front Immunol. 2025;16:1590822. Published 2025 Jul 10. doi:10.3389/fimmu.2025.1590822
3. Halbgebauer R, Schult L, Borgel O, et al. Pathophysiological response in trauma-related acute kidney injury after blunt thoracic trauma and hemorrhagic shock in male mice.Am J Physiol Renal Physiol. 2025;329(2):F311-F322. doi:10.1152/ajprenal.00029.2025
4. Messerer DAC, Halbgebauer R, Nilsson B, Pavenstädt H, Radermacher P, Huber-Lang M. Immunopathophysiology of trauma-related acute kidney injury. Nat Rev Nephrol. 2021;17(2):91-111. doi:10.1038/s41581-020-00344-9
5. Zhao ZB, Marschner JA, Iwakura T, et al. Tubular Epithelial Cell HMGB1 Promotes AKI-CKD Transition by Sensitizing Cycling Tubular Cells to Oxidative Stress: A Rationale for Targeting HMGB1 during AKI Recovery. J Am Soc Nephrol. 2023;34(3):394-411. doi:10.1681/ASN.0000000000000024
6. Liu T, Xiang A, Peng T, et al. HMGB1-C1q complexes regulate macrophage function by switching between leukotriene and specialized proresolving mediator biosynthesis.Proc Natl Acad Sci U S A. 2019;116(46):23254-23263. doi:10.1073/pnas.1907490116
7. Su C, Jia S, Ma Z, Zhang H, Wei L, Liu H. HMGB1 Promotes Lymphangiogenesis through the Activation of RAGE on M2 Macrophages in Laryngeal Squamous Cell Carcinoma.Dis Markers. 2022;2022:4487435. Published 2022 Mar 4. doi:10.1155/2022/4487435
8. Baranwal G, Creed HA, Black LM, et al. Expanded renal lymphatics improve recovery following kidney injury.Physiol Rep. 2021;9(22):e15094. doi:10.14814/phy2.15094