Study summary · research use only
Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study in rats and in HK-2 kidney cells investigated Hexarelin's effects on ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Rats were pretreated with Hexarelin at 100 μg/kg/d for 7 days before ischemia/reperfusion injury and assessed 24 h later for kidney function, histology, and apoptosis; a hypoxia/reoxygenation model in HK-2 cells was also used. Hexarelin pretreatment reduced post-ischemic kidney pathological changes, was associated with improved renal function markers, and reduced apoptosis, along with downregulation of Caspase-3, Bax, and Bad and upregulation of Bcl-2; similar reductions in apoptosis occurred in HK-2 cells. Molecular docking showed binding between Hexarelin and MDM2, and the authors report reduced MDM2 and p53 expression with Hexarelin pretreatment in both models, describing Hexarelin's anti-apoptotic effect as potentially acting through MDM2.
Abstract
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. 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. 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. Collectively, Hexarelin was identified as a promising medication in protecting apoptosis against I/R-induced AKI.
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