Inhibition of high mobility group box 1 (HMGB1) attenuates podocyte apoptosis and epithelial‐mesenchymal transition by regulating autophagy flux

Jin, Juan; Gong, Jianguang; Zhao, Li; Zhang, Hongjuan; He, Qiang; Jiang, Xinxin

doi:10.1111/1753-0407.12914

Cited by 25 publications

(24 citation statements)

References 40 publications

(72 reference statements)

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“…HMGB1 is a damage-related molecular pattern that can be actively or passively released from various cells under different conditions and plays a key role in the pathogenesis of inflammation and angiogenesis-dependent diseases (33). Additionally, HMGB1 is involved in the development of T2DM by inducing autophagy (34), and HMGB1 deletion can inhibit podocyte EMT by inhibiting TGF-β/smad1 signaling (35).…”

Section: Mir-92d-3p Suppressed the Progression Of Dn Disease By Inhibiting The Activationmentioning

confidence: 99%

MiR-92d-3p suppresses the progression of diabetic nephropathy renal fibrosis by inhibiting the C3/HMGB1/TGF-β1 pathway

Zhang

2021

Bioscience Reports

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The pathogenesis of diabetic nephropathy (DN) has not been fully elucidated. MicroRNAs play an important role in the onset and development of DN renal fibrosis. Thus, this study aimed to investigate the effect of miR-92d-3p on the progression of DN renal fibrosis. We used qRT-PCR to detect the expression levels of miR-92d-3p in the kidneys of patients with DN. Then, after transfecting lentiviruses containing miR-92d-3p into the kidneys of a DN mouse model and HK-2 cell line, we used qRT-PCR to detect the expression levels of miR-92d-3p, C3, HMGB1, TGF-β1, α-SMA, E-cadherin, and Col Ⅰ. The expression levels of IL-1β, IL-6, and TNF-α in the HK-2 cells were detected through enzyme-linked immunosorbent assay, and Western blotting and immunofluorescence were used in detecting the expression levels of fibronectin, α-SMA, E-cadherin, and vimentin. Results showed that the expression levels of miR-92d-3p in the kidney tissues of patients with DN and DN animal model mice decreased, and C3 stimulated HK-2 cells to produce inflammatory cytokines. The C3/HMGB1/TGF-β1 pathway was activated, and EMT was induced in the HK-2 cells after human recombinant C3 and TGF-β1 protein were added. miR-92d-3p inhibited inflammatory factor production by C3 in the HK-2 cells and the activation of the C3/HMGB1/TGF-β1 pathway and EMT by C3 and TGF-β1. miR-92d-3p suppressed the progression of DN renal fibrosis by inhibiting the activation of the C3/HMGB1/TGF-β1 pathway and EMT.

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Section: Mir-92d-3p Suppressed the Progression Of Dn Disease By Inhibiting The Activationmentioning

confidence: 99%

MiR-92d-3p suppresses the progression of diabetic nephropathy renal fibrosis by inhibiting the C3/HMGB1/TGF-β1 pathway

Zhang

2021

Bioscience Reports

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“…In this study, we proposed that the molecular mechanism behind the effect of CLEC14A on the regulation of inflammatory response is most likely related to its ability to inhibit HMGB1 signaling. Emerging evidence has indicated that HMGB1 is involved in podocyte injury 25,26 . HMGB1 is a DNA‐binding nuclear protein, released actively following cytokine stimulation and passively during cell injury and death.…”

Section: Discussionmentioning

confidence: 99%

CLEC14A protects against podocyte injury in mice with adriamycin nephropathy

et al. 2021

The FASEB Journal

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Podocyte injury is a major determinant of focal segmental glomerular sclerosis (FSGS) and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance for the treatment of FSGS. CLEC14A is a single‐pass transmembrane glycoprotein belonging to the vascular expressed C‐type lectin family. CLEC14A is found to be expressed in vascular endothelial cells during embryogenesis and is also implicated in tumor angiogenesis. However, the current understanding of the biological functions of CLEC14A in podocyte is very limited. In this study, we found that CLEC14A was expressed in podocyte and protected against podocyte injury in mice with Adriamycin (ADR)‐induced FSGS. First, we observed that CLEC14A was downregulated in mice with ADR nephropathy and renal biopsies from individuals with FSGS and other forms of podocytopathies. Moreover, CLEC14A deficiency exacerbated podocyte injury and proteinuria in mice with ADR nephropathy accompanied by enhanced inflammatory cell infiltration and inflammatory responses. In vitro, overexpression of CLEC14A in podocyte had pleiotropic protective actions, including anti‐inflammatory and anti‐apoptosis effects. Mechanistically, CLEC14A inhibited high‐mobility group box 1 protein (HMGB1) release, at least in part by directly binding HMGB1, and suppressed HMGB1‐mediated signaling, including NF‐κB signaling and early growth response protein 1 (EGR1) signaling. Taken together, our findings provide new insights into the pivotal role of CLEC14A in maintaining podocyte function, indicating that CLEC14A may be an innovative therapeutic target in FSGS.

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“…Interestingly, Jin and colleagues [53] studied the effect of STIM1 on autophagy and epithelial-mesenchymal transition (EMT) in podocytes in diabetic nephropathy. They found that, in podocytes cultured in the serum of diabetic nephrotic rats, autophagy decreased, whereas EMT increased and that both changes reverse after silencing STIM1.…”

Section: Discussionmentioning

confidence: 99%

Role of calcium in adult onset polycystic kidney disease

Yanda

Liu

Cebotaru

et al. 2019

Cellular Signalling

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in genes encoding the polycystin (PC) 1 and 2 proteins. The goal of this study was to determine the role of calcium in regulating cyst growth. Stromal interaction molecule 1 (STIM1) protein expression was 15-fold higher in PC1-null proximal tubule cells (PN) than in heterozygote (PH) controls and 2-fold higher in an inducible, PC1 knockout, mouse model of ADPKD compared to a non-cystic match control. IP3 receptor protein expression was also higher in the cystic mice. Knocking down STIM1 with siRNA reduced cyst growth and lowered cAMP levels in PN cells. Fura2 measurements of intracellular Ca2+ showed a dramatic reduction in thapsigargin-stimulated release of ER Ca2+ following STIM1 silencing or application of 2-APB, consistent with altered ER Ca2+ movement; the protein expression of the Ca2+-dependent adenylyl cyclases (AC) AC3 and AC6 was up- and down-regulated, respectively. Like STIM1 knockdown, application of the calmodulin inhibitor W7 lowered cAMP levels, further indicating that STIM1 regulates AC3 via Ca2+ We conclude that the high levels of STIM1 in ADPKD cells play a role in supporting cyst growth and promoting high cAMP levels and an increased release of Ca2+ from the ER. Thus, our results provide novel therapeutic targets for treating ADPKD.

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Inhibition of high mobility group box 1 (HMGB1) attenuates podocyte apoptosis and epithelial‐mesenchymal transition by regulating autophagy flux

Cited by 25 publications

References 40 publications

MiR-92d-3p suppresses the progression of diabetic nephropathy renal fibrosis by inhibiting the C3/HMGB1/TGF-β1 pathway

MiR-92d-3p suppresses the progression of diabetic nephropathy renal fibrosis by inhibiting the C3/HMGB1/TGF-β1 pathway

CLEC14A protects against podocyte injury in mice with adriamycin nephropathy

Role of calcium in adult onset polycystic kidney disease

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