Release of HMGB1 in Podocytes Exacerbates Lipopolysaccharide-Induced Acute Kidney Injury

Abstract

Objective. Acute kidney injury (AKI) usually occurs during sepsis. Inflammation factors, such as high-mobility group box 1 (HMGB1), are dramatically upregulated under septic conditions. In our current work, the functions of HMGB1 in AKI were explored. Methods. An AKI model was induced by the lipopolysaccharide (LPS) challenge in C57 mice. Podocytes were challenged by LPS for different durations. Subsequently, podocytes transfected with HMGB1 siRNA were exposed to LPS for 24 h. The expressions of supernatant HMGB1 and cellular active caspase-3 were examined by Western blotting analysis. To explore the effect of HMGB1 on tubular epithelial cells (TECs), HK-2 cells were exposed to HMGB1 at various concentrations for 24 h. Epithelial-mesenchymal transition (EMT) of HK-2 cells was evaluated by Western blotting analysis. Mitochondrial division and apoptosis of HK-2 cells were assessed by MitoTracker Red and Western blotting analysis, respectively. Results. Compared with the sham control group, the expression of HMGB1 was increased in the kidney of AKI mice. Moreover, the expression of supernatant HMGB1 was increased in LPS-challenged podocytes compared with the control group. Knockdown of HMGB1 attenuated LPS-induced podocyte injury. Besides, EMT in TECs was triggered by HMGB1. Mitochondrial damage and apoptosis of HK-2 cells exposed to HMGB1 were markedly elevated compared with the control group. Conclusions. Collectively, HMGB1 release in podocytes was induced by LPS, subsequently leading to exacerbated AKI.

HMGB1 is a critical molecule in the pathogenesis of Gram-negative sepsis

“… [72] It has been demonstrated that LPS damages podocytes, which constitute the glomerular filtration barrier. [ 73 , 74 ] Knockdown of HMGB1 attenuates the endotoxin-induced injury in cultured podocytes. [73] Furthermore, tubular epithelial cells express mitochondrial dysfunction after HMGB1 exposure.…”

“…[ 73 , 74 ] Knockdown of HMGB1 attenuates the endotoxin-induced injury in cultured podocytes. [73] Furthermore, tubular epithelial cells express mitochondrial dysfunction after HMGB1 exposure. [73] Another study reports that HMGB1 accumulates in renal tissue during Gram-negative sepsis and enters the urine, and the interaction between HMGB1 and TLR4 turns tubular epithelial cells into inflammatory promoters.…”

“… [73] Furthermore, tubular epithelial cells express mitochondrial dysfunction after HMGB1 exposure. [73] Another study reports that HMGB1 accumulates in renal tissue during Gram-negative sepsis and enters the urine, and the interaction between HMGB1 and TLR4 turns tubular epithelial cells into inflammatory promoters. [75] Further support for the perception that HMGB1 plays an important role in the development of acute kidney injury is provided by results establishing that SIRT1-mediated HMGB1 deacetylation that subsequently inhibited HMGB1 release also ameliorated sepsis-associated acute kidney injury.…”

Determination of HMGB1 in hepatitis B virus-related acute-on-chronic liver failure patients with acute kidney injury: Early prediction and prognostic implications

“…Infection accompanied by the release of HMGB1 contributes to circulatory dysfunction and is one of the major contributing factors of AKI. Experimental studies have shown that HMGB1 release from podocytes is induced by lipopolysaccharide (LPS), which subsequently exacerbates AKI (Gao et al, 2021). The release of HMGB1 worsened circulatory dysfunction.…”

The Intersection of Acute Kidney Injury and Non-Coding RNAs: Inflammation

“…In ischemic AKI, the aseptic inflammatory response associated with damage-associated molecular patterns (DAMPs) is considered one of the first pathological processes ( Hepokoski et al, 2021 ; Liu et al, 2021 ). Renal tubular cell necrosis releases intracellular molecules such as high mobility group box 1 (HMGB1), histones, heat kinin, and fibronectin into the extracellular space and activates recognition receptors on either tissue-resident cells or recruited leukocytes via the DAMPs ( Wang et al, 2020c ; Gao et al, 2021 ). Cell necrosis then leads to a massive secretion of pro-inflammatory cytokines and chemokines, further aggravating the inflammatory cascade response.…”