SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model
Autor: | Yunhe Zhang, Chun-Shiang Chung, Alfred Ayala, Elizabeth W Tindal, Baoji Hu, Jihong Jiang, Yaping Chen, Jinbao Li |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Male
0301 basic medicine Chemokine Phosphatase inhibition Biopsy medicine.medical_treatment Protein Tyrosine Phosphatase Non-Receptor Type 11 STAT3 Mice 0302 clinical medicine lcsh:QD415-436 PHPS1 Genetics (clinical) Mitogen-Activated Protein Kinase 1 Kidney Mitogen-Activated Protein Kinase 3 biology Benzenesulfonates Acute kidney injury Shock medicine.anatomical_structure Cytokine Cytokines Molecular Medicine Disease Susceptibility Inflammation Mediators Research Article STAT3 Transcription Factor medicine.medical_specialty Phosphatase Hemorrhage HMGB1 Proinflammatory cytokine Sepsis lcsh:Biochemistry 03 medical and health sciences AKI Erk1/2 Internal medicine Genetics medicine Animals Molecular Biology business.industry lcsh:RM1-950 Hydrazones 030208 emergency & critical care medicine medicine.disease 030104 developmental biology Endocrinology lcsh:Therapeutics. Pharmacology biology.protein SHP2 business Biomarkers |
Zdroj: | Molecular Medicine, Vol 26, Iss 1, Pp 1-12 (2020) Molecular Medicine |
ISSN: | 1528-3658 1076-1551 |
Popis: | 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 believe this is a potentially important finding with clinical implications warranting further investigation. |
Databáze: | OpenAIRE |
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