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A novel GSK3β inhibitor 5n attenuates acute kidney injury
Yu-Ting Cai1, Zeng Li2, Yue-Yue Wang2
1Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China.
Abstract:
Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality caused by various factor. The specific strategies for AKI are still lacking. GSK3β is widely expressed in the kidneys. In acute models of injury, GSK3β promotes the systemic inflammatory response, increases the proinflammatory release of cytokines, induces apoptosis, and alters cell proliferation. We screened a series of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives which are recognized as new GSK3β inhibitors, and found that 5n had the least toxicity and the best cell protection. We then tested the anti-inflammatory and reno-protective effect of 5n in cisplatin-treated tubular epithelial cells. 5n had anti-inflammation effect indicated by phosphor-NF-κB detection. Finally, we found that 5n ameliorated renal injury and inflammation in cisplatin-induced AKI mouse model. Silencing GSK3β inhibited cell injury and inflammation induced by cisplatin. We found that GSK3β interacted with PP2Ac to modulate the activity of NF-κB. In conclusion, 5n, the novel GSK3β inhibitor, protects against AKI via PP2Ac-dependent mechanisms which may provide a potential strategy for the treatment of AKI in clinic.
Insights
A novel GSK3β inhibitor, 5n, demonstrates significant protective effects against acute kidney injury (AKI). This compound reduces inflammation and cell damage, offering a potential new therapeutic strategy for AKI treatment.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Acute kidney injury (AKI) presents a significant clinical challenge with limited targeted treatments.
- Glycogen synthase kinase 3 beta (GSK3β) plays a detrimental role in kidney injury by promoting inflammation and apoptosis.
Purpose of the Study:
- To investigate the renoprotective and anti-inflammatory effects of novel GSK3β inhibitors.
- To evaluate the therapeutic potential of compound 5n in acute kidney injury models.
Main Methods:
- Screening of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives as GSK3β inhibitors.
- In vitro testing of compound 5n in cisplatin-treated tubular epithelial cells.
- In vivo evaluation of 5n in a cisplatin-induced AKI mouse model.
- Analysis of GSK3β interaction with PP2Ac and modulation of NF-κB signaling.
Main Results:
- Compound 5n exhibited low toxicity and potent cell-protective properties.
- 5n demonstrated anti-inflammatory effects by reducing phosphor-NF-κB levels.
- 5n ameliorated renal injury and inflammation in a mouse model of cisplatin-induced AKI.
- GSK3β silencing inhibited cisplatin-induced kidney injury and inflammation.
Conclusions:
- Compound 5n, a novel GSK3β inhibitor, effectively protects against AKI.
- The protective mechanism involves PP2Ac-dependent modulation of NF-κB signaling.
- 5n represents a promising therapeutic candidate for clinical AKI treatment.
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