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
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
Externí odkaz: