Heme oxygenase-1 induction mitigates burn-associated early acute kidney injury via the TLR4 signaling pathway

  • Burns. 2022 Feb;48(1):156-167. doi: 10.1016/j.burns.2021.04.013.
Songxue Guo  1 ,  Meirong Yu  2 ,  Quan Fang  1 ,  Liping Zhang  3 ,  Chuangang You  3 ,  Xingang Wang  3 ,  Yong Liu  4 ,  Chunmao Han  5
Affiliations
  • 1. Department of Plastic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, 1511 Jianghong Road, Hangzhou 310000, Zhejiang, China.
  • 2. Clinical Research Center, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China.
  • 3. Department of Burns, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China.
  • 4. Department of Burns and Plastic Surgery, West China Hospital Sichuan University, 37 Guoxuexiang St., Chengdu 610041, Sichuan, China.
  • 5. Department of Burns, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China. Electronic address: [email protected].
PMID: 33962830 DOI: 10.1016/j.burns.2021.04.013
Abstract

Objectives: Early acute kidney injury (AKI) after burn contributes to disastrous prognoses for severely burned patients. Burn-induced renal oxidative stress and secondary proinflammatory mediator release contribute to early AKI development, and Toll-like Receptor (TLR) 4 regulates inflammation. Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that plays a vital role in protecting against ischemia-induced organ injury via its antioxidant properties and regulation of inflammation. We investigated the potential effect of HO-1 induction in preventing burn-induced early AKI and its related mechanism.

Methods: A classic major-burn rat model was established using a 100 °C water bath, and hemin was injected intraperitoneally immediately after the injury to induce HO-1. Histological staining and blood tests were used to assess AKI progression based on structural changes and function. Renal levels of HO-1, oxidative stress, proinflammatory mediators and TLR4-related signals were detected using ELISA, immunostaining, qRT-PCR, and western blotting. The selective TLR4 Inhibitor TAK242 and TLR4 Inducer LPS were introduced to determine the roles of HO-1 in burn-related renal inflammation and the TLR4 pathway.

Results: Hemin improved burn-induced renal histological damage and dysfunction, and this beneficial effect was related to reduced renal oxidative stress and the release of proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and intracellular adhesion molecule-1 (ICAM-1). Hemin downregulated the expression of TLR4 and the subsequent phosphorylation of IKKα/β, IκBα, and NF-κB p65;. TAK242 exerted an effect similar to but weaker than hemin; and LPS reversed the antiinflammatory effect of hemin and the regulation of TLR4 signals. These results suggested that the TLR4 signaling pathway mediated the HO-1-facilitated regulation of renal inflammation after burn.

Conclusion: The present study demonstrated that HO-1 induction prevented burn-induced early AKI by targeting renal inflammation, which was mediated via regulation of the TLR4/NF-κB signaling pathway.

Keywords
Acute kidney injury; Burns; Heme oxygenase-1; Inflammation; Oxidative stress; Toll-like receptor.
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