Clinical science (1979), 2019-07, Vol.133 (14), p.1609-1627
2019
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- Autor(en) / Beteiligte
- Titel
- RIPK1 inhibitor Cpd-71 attenuates renal dysfunction in cisplatin-treated mice via attenuating necroptosis, inflammation and oxidative stress
- Ist Teil von
- Clinical science (1979), 2019-07, Vol.133 (14), p.1609-1627
- Ort / Verlag
- England
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, and Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0143-5221eISSN: 1470-8736DOI: 10.1042/cs20190599Titel-ID: cdi_pubmed_primary_31315969
- Format
- –
- Schlagworte
- Acute Kidney Injury - drug therapy, Acute Kidney Injury - genetics, Acute Kidney Injury - immunology, Acute Kidney Injury - physiopathology, Animals, Antineoplastic Agents - administration & dosage, Cisplatin - adverse effects, Humans, Kidney - drug effects, Kidney - enzymology, Kidney - immunology, Male, Mice, Mice, Inbred C57BL, Necroptosis - drug effects, Oxidative Stress - drug effects, Protein Kinase Inhibitors - administration & dosage, Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors, Receptor-Interacting Protein Serine-Threonine Kinases - genetics, Receptor-Interacting Protein Serine-Threonine Kinases - immunology