PMID- 32957908 OWN - NLM STAT- MEDLINE DCOM- 20210810 LR - 20240429 IS - 1528-3658 (Electronic) IS - 1076-1551 (Print) IS - 1076-1551 (Linking) VI - 26 IP - 1 DP - 2020 Sep 21 TI - SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model. PG - 89 LID - 10.1186/s10020-020-00210-1 [doi] LID - 89 AB - 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. FAU - Jiang, Jihong AU - Jiang J AD - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, P.R. China. FAU - Hu, Baoji AU - Hu B AD - Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University-Pudong Medical Center, Shanghai, 200433, P.R. China. FAU - Chung, Chun-Shiang AU - Chung CS AD - Division of Surgical Research, Department of Surgery, Aldrich 227, Rhode Island Hospital/ the Alpert School of Medicine at Brown University, 593 Eddy Street, Providence, RI, 02903, USA. FAU - Chen, Yaping AU - Chen Y AD - Division of Surgical Research, Department of Surgery, Aldrich 227, Rhode Island Hospital/ the Alpert School of Medicine at Brown University, 593 Eddy Street, Providence, RI, 02903, USA. FAU - Zhang, Yunhe AU - Zhang Y AD - Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, P.R. China. FAU - Tindal, Elizabeth W AU - Tindal EW AD - Division of Surgical Research, Department of Surgery, Aldrich 227, Rhode Island Hospital/ the Alpert School of Medicine at Brown University, 593 Eddy Street, Providence, RI, 02903, USA. FAU - Li, Jinbao AU - Li J AD - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, P.R. China. FAU - Ayala, Alfred AU - Ayala A AUID- ORCID: 0000-0002-5034-2995 AD - Division of Surgical Research, Department of Surgery, Aldrich 227, Rhode Island Hospital/ the Alpert School of Medicine at Brown University, 593 Eddy Street, Providence, RI, 02903, USA. aayala@lifespan.org. LA - eng GR - P20 RR017695/RR/NCRR NIH HHS/United States GR - R35 GM118097/GM/NIGMS NIH HHS/United States GR - P30 GM110759/GM/NIGMS NIH HHS/United States GR - P20 GM103421/GM/NIGMS NIH HHS/United States GR - T32 GM065085/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200921 PL - England TA - Mol Med JT - Molecular medicine (Cambridge, Mass.) JID - 9501023 RN - 0 (Benzenesulfonates) RN - 0 (Biomarkers) RN - 0 (Cytokines) RN - 0 (Hydrazones) RN - 0 (Inflammation Mediators) RN - 0 (STAT3 Transcription Factor) RN - 0 (phenylhydrazonopyrazolone sulfonate 1) RN - EC 2.7.11.24 (Mapk1 protein, mouse) RN - EC 2.7.11.24 (Mapk3 protein, mouse) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) RN - EC 3.1.3.48 (Ptpn11 protein, mouse) SB - IM MH - Acute Kidney Injury/diagnosis/drug therapy/*etiology/*metabolism MH - Animals MH - Benzenesulfonates/*pharmacology MH - Biomarkers MH - Biopsy MH - Cytokines/metabolism MH - Disease Susceptibility MH - Hemorrhage/complications MH - Hydrazones/*pharmacology MH - Inflammation Mediators/metabolism MH - Male MH - Mice MH - Mitogen-Activated Protein Kinase 1/*metabolism MH - Mitogen-Activated Protein Kinase 3/*metabolism MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*antagonists & inhibitors MH - STAT3 Transcription Factor/*metabolism MH - Sepsis/complications PMC - PMC7504828 OTO - NOTNLM OT - AKI OT - Acute kidney injury OT - Erk1/2 OT - Hemorrhage OT - PHPS1 OT - Phosphatase inhibition OT - SHP2 OT - STAT3 OT - Sepsis OT - Shock COIS- The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. EDAT- 2020/09/23 06:00 MHDA- 2021/08/11 06:00 PMCR- 2020/09/21 CRDT- 2020/09/22 05:30 PHST- 2020/04/08 00:00 [received] PHST- 2020/08/07 00:00 [accepted] PHST- 2020/09/22 05:30 [entrez] PHST- 2020/09/23 06:00 [pubmed] PHST- 2021/08/11 06:00 [medline] PHST- 2020/09/21 00:00 [pmc-release] AID - 10.1186/s10020-020-00210-1 [pii] AID - 210 [pii] AID - 10.1186/s10020-020-00210-1 [doi] PST - epublish SO - Mol Med. 2020 Sep 21;26(1):89. doi: 10.1186/s10020-020-00210-1.