Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway.

Abstract

INTRODUCTION:

Hexarelin exhibits significant protection against organ injury in models of ischemia/reperfusion (I/R)-induced injury (IRI). Nevertheless, the impact of Hexarelin on acute kidney injury (AKI) and its underlying mechanism remains unclear. In this study, we investigated the therapeutic potential of Hexarelin in I/R-induced AKI and elucidated its molecular mechanisms.

METHODS:

We assessed the protective effects of Hexarelin through both in vivo and in vitro experiments. In the I/R-induced AKI model, rats were pretreated with Hexarelin at 100 μg/kg/d for 7 days before being sacrificed 24 h post-IRI. Subsequently, kidney function, histology, and apoptosis were assessed. In vitro, hypoxia/reoxygenation (H/R)-induced HK-2 cell model was used to investigate the impact of Hexarelin on apoptosis in HK-2 cells. Then, we employed molecular docking using a pharmmapper server and autodock software to identify potential target proteins of Hexarelin.

RESULTS:

In this study, rats subjected to I/R developed severe kidney injury characterized by tubular necrosis, tubular dilatation, increased serum creatinine levels, and cell apoptosis. However, pretreatment with Hexarelin exhibited a protective effect by mitigating post-ischemic kidney pathological changes, improving renal function, and inhibiting apoptosis. This was achieved through the downregulation of conventional apoptosis-related genes, such as Caspase-3, Bax and Bad, and the upregulation of the anti-apoptotic protein Bcl-2. Consistent with the in vivo results, Hexarelin also reduced cell apoptosis in post-H/R HK-2 cells. Furthermore, our analysis using GSEA confirmed the essential role of the apoptosis pathway in I/R-induced AKI. Molecular docking revealed a strong binding affinity between Hexarelin and MDM2, suggesting the potential mechanism of Hexarelin's anti-apoptosis effect at least partially through its interaction with MDM2, a well-known negative regulator of apoptosis-related protein that of p53. To validate these findings, we evaluated the relative expression of MDM2 and p53 in I/R-induced AKI with or without Hexarelin pre-administration and observed a significant suppression of MDM2 and p53 by Hexarelin in both in vivo and in vitro experiments.

CONCLUSION:

Collectively, Hexarelin was identified as a promising medication in protecting apoptosis against I/R-induced AKI.

• Authors: Chen Guan, Chenyu Li, Xuefei Shen, Chengyu Yang, Zengying Liu, Ningxin Zhang, Lingyu Xu, Long Zhao, Bin Zhou, Xiaofei Man, Congjuan Luo, Hong Luan, Lin Che, Yanfei Wang, Yan Xu
• Journal: European journal of medical research (Eur J Med Res) Vol. 28 Issue 1 Pg. 344 (Sep 14 2023) ISSN: 2047-783X [Electronic] England
• PMID: 37710348 (Publication Type: Journal Article)
• Copyright: © 2023. BioMed Central Ltd., part of Springer Nature.

Chemical References

• hexarelin
• Tumor Suppressor Protein p53

Topics

• Animals
• Rats
• Tumor Suppressor Protein p53 (genetics)
• Molecular Docking Simulation
• Acute Kidney Injury (drug therapy)
• Reperfusion Injury (drug therapy)
• Ischemia