High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics

Vijayakumar, Eyaldeva C; Bhatt, Lokesh Kumar; Prabhavalkar, Kedar

doi:10.2174/1389450120666190618125100

Cited by 62 publications

(52 citation statements)

References 144 publications

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“…PHPS1 treatment suppresses the Hem/CLP-induced expression of HMGB1 in the kidney. HMGB1, as a late lethal inflammatory mediator, is reported to play an important role in sepsis course (Vijayakumar et al 2019, Wang et al 2001. We observed a significant upregulation of HMGB1 in the renal tissue of Hem/CLP group mice that was also abrogated in the PHPS1 treated Hem/CLP group (Fig.…”

Section: Resultsmentioning

confidence: 51%

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a hemorrhage followed CLP mice model

Jiang¹,

Hu²,

Chung³

et al. 2020

Preprint

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Background Hypovolemic shock and septic challenge are two major causes of acute kidney injury (AKI) in the clinic course. Src homology 2 domain-containing phosphatase 2 (SHP2) is one of the major phosphatase protein tyrosine phosphatase (PTPs), which play a significant role in maintaining immunological homeostasis by regulating many facets of immune cell signaling. In this study, we explored whether SHP2 signaling contributed to AKI induced by hemorrhage (Hem) followed by cecal ligation and puncture (CLP) (Hem/CLP) and, further, if inactivation of SHP2 with the selective inhibitor, Phenylhydrazonopyrazolone sulfonate 1 (PHPS1), attenuated this injury. Methods Male C57BL/6 mice were subjected to Hem (a “priming” insult) followed by CLP or sham-Hem plus sham-CLP (S/S) as controls. Samples of blood and kidney were harvested at 24 h post CLP. The expression of neutrophil gelatinase-associated lipocalin (NGAL), high mobility group box 1 (HMGB1), caspase3 as well as SHP2:phospho-SHP2, extracellular-regulated kinase (Erk1/2):phospho-Erk1/2, and signal transducer and activator of transcription 3 (STAT3):phospho-STAT3 protein in kidney tissues were detected by Western blotting. The levels of creatinine (Cre) and blood urea nitrogen (BUN) in serum were measured according to the manufacturer’s instructions. Blood inflammatory cytokine/chemokine levels were detected by ELISA. Results Here we report that indices of kidney injury, such as BUN, Cre, NGAL in renal tissue and histopathologic change, were pronounced after Hem/CLP in comparison with that observed in the S/S group mice. Furthermore, while Hem/CLP elevated serum levels of inflammatory cytokine/ chemokine, and induced increased levels of HMGB1, SHP2:phospho-SHP2, Erk1/2:phospho-Erk1/2, as well asSTAT3:phospho-STAT3 protein expression in the kidney; treatment with PHPS1 markedly attenuated these Hem/CLP induced changes. Conclusions In conclusion, our data indicate that SHP2 inhibition attenuates AKI induced by our double-hit/sequential insult model of Hem/CLP and that this protective action may be attributable to its anti-inflammatory property in mitigating activation of the Erk1/2 and STAT3 signaling pathway. This finding we believe has important potential clinical implications and, thus, warrants further investigation.

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Section: Resultsmentioning

confidence: 51%

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a hemorrhage followed CLP mice model

Jiang¹,

Hu²,

Chung³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…HMGB1, as a late lethal in ammatory mediator, is reported to play an important role in sepsis outcomes (Vijayakumar et al 2019, Wang et al 2001. We observed a signi cant upregulation of HMGB1 in the renal tissue of Hem/CLP group mice that was also reversed with PHPS1 treatment ( Figure 6).…”

Section: Resultsmentioning

confidence: 99%

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model.

Jiang

Chung

et al. 2020

Preprint

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Background: Hypovolemic shock and septic challenge are two major causes of acute kidney injury (AKI) in the clinic setting. Src homology 2 domain-containing phosphatase 2 (SHP2) is one of the major protein phosphatase tyrosine phosphatase (PTPs), which play a significant role in maintaining immunological homeostasis by regulating many facets of immune cell signaling. In this study, we explored whether SHP2 signaling contributed to development of AKI sequential hemorrhage (Hem) and cecal ligation and puncture (CLP) and whether inactivation of SHP2 through administration of its selective inhibitor, phenylhydrazonopyrazolone sulfonate 1 (PHPS1), attenuated this injury.Methods: Male C57BL/6 mice were subjected to Hem (a “priming” insult) followed by CLP or sham-Hem plus sham-CLP (S/S) as controls. Samples of blood and kidney were harvested at 24 h post CLP. The expression of neutrophil gelatinase-associated lipocalin (NGAL) , high mobility group box 1 ( HMGB1 ), caspase3 as well as SHP2:phospho-SHP2, extracellular-regulated kinase (Erk1/2) :phospho-Erk1/2, and signal transducer and activator of transcription 3 (STAT3):phospho-STAT3 protein in kidney tissues were detected by Western blotting. The levels of creatinine (Cre) and blood urea nitrogen (BUN) in serum were measured according to the manufacturer’s instructions. Blood inflammatory cytokine/chemokine levels were detected by ELISA.Results: We found that indices of kidney injury, including levels of BUN, Cre and NGAL as well as histopathologic changes, were significantly increased after Hem/CLP in comparison with that in the S/S group. Furthermore, Hem/CLP resulted in elevated serum levels of inflammatory cytokines/chemokines, and induced increased levels of HMGB1, SHP2:phospho-SHP2, Erk1/2:phospho-Erk1/2, and STAT3:phospho-STAT3 protein expression in the kidney. Treatment with PHPS1 markedly attenuated these Hem/CLP-induced changes.Conclusions: In conclusion, our data indicate that SHP2 inhibition attenuates AKI induced by our double-hit/sequential insult model of Hem/CLP and that this protective action may be attributable to its ability to mitigate activation of the Erk1/2 and STAT3 signaling pathway. We believethis is a potentially important finding with clinical implications warranting further investigation.

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“…Translocation of HMGB1 from the nucleus to the cytoplasm and subsequent release to the extracellular milieu is reported to promote inflammatory response via the activation of TLRs (Yang et al, 2010). HMGB1-TLRs pathway has long been recognized as an essential and early mediator in renal IRI and an attractive target of AKI and other disease therapies (Li et al, 2011;Zhang et al, 2016;Vijayakumar et al, 2019).…”

Section: Role Of Fgfs On Inflammationmentioning

confidence: 99%

Fibroblast Growth Factors in the Management of Acute Kidney Injury Following Ischemia-Reperfusion

et al. 2020

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Ischemia-reperfusion injury (IRI), which is triggered by a transient reduction or cessation of blood flow followed by reperfusion, is a significant cause of acute kidney injury (AKI). IRI can lead to acute cell death, tissue injury, and even permanent organ dysfunction. In the clinic, IRI contributes to a higher morbidity and mortality and is associated with an unfavorable prognosis in AKI patients. Unfortunately, effective clinical drugs to protect patients against the imminent risk of renal IRI or treat already existing AKI are still lacking. Fibroblast growth factors (FGFs) are important regulators of key biological and pathological processes, such as embryonic development, metabolic homeostasis and tumorigenesis through the regulation of cell differentiation, migration, proliferation and survival. Accumulating evidence suggests that altered expression of endogenous FGFs is associated with IRI and could be instrumental in mediating the repair process. Therefore, FGFs have been proposed as potential biomarkers in the clinic. More importantly, exogenous FGF ligands have been reported to protect against renal IRI and display promising features for therapy. In this review, we summarize the evidence and mechanisms of AKI following IRI with a focus on the therapeutic capacity of several members of the FGF family to treat AKI after IRI.

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High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics

Cited by 62 publications

References 144 publications

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a hemorrhage followed CLP mice model

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a hemorrhage followed CLP mice model

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model.

Fibroblast Growth Factors in the Management of Acute Kidney Injury Following Ischemia-Reperfusion

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