Alpha-cyperone mitigates renal ischemic injury via modulation of HDAC-2 expression in diabetes: Insights from molecular dynamics simulations and experimental evaluation

• Published in: European journal of pharmacology 2024-07, Vol.975, p.176643-176643, Article 176643
• Main Authors: Daude, Rakesh B., Bhadane, Rajendra, Shah, Jigna S.
• Format: Article
• Language: English
• Subjects: Alpha-cyperone; Animals; Cell Line; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; Histone Deacetylase 2 - metabolism; Histone deacetylase-2; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Molecular Docking Simulation; Molecular Dynamics Simulation; Oxidative Stress - drug effects; Rats; Rats, Wistar; Renal ischemia/reperfusion injury; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2024.176643

Chronic diabetes mellitus is reported to be associated with acute kidney injury. The enzyme histone deacetylase-2 (HDAC-2) was found to be upregulated in diabetes-related kidney damage. Alpha-cyperone (α-CYP) is one of the active ingredients of Cyperus rotundus that possesses antioxidant and anti-inflammatory effects. We evaluated the effect of α-CYP on improving oxidative stress and tissue inflammation following renal ischemia/reperfusion (I/R) injury in diabetic rats. The effect of α-CYP on HDAC-2 expression in renal homogenates and in the NRK-52 E cell line was evaluated following renal I/R injury and high glucose conditions, respectively. Molecular docking was used to investigate the binding of α-CYP with the HDAC-2 active site. Both renal function and oxidative stress were shown to be impaired in diabetic rats due to renal I/R injury. Significant improvements in kidney/body weight ratio, creatinine clearance, serum creatinine, blood urea nitrogen (BUN), and uric acid were observed in diabetic rats treated with α-CYP (50 mg/kg) two weeks prior to renal I/R injury. α-CYP treatment also improved histological alterations in renal tissue and lowered levels of malondialdehyde, myeloperoxidase, and hydroxyproline. Treatment with α-CYP suppressed the increased HDAC-2 expression in the renal tissue of diabetic rats and in the NRK-52 E cell line. The molecular docking reveals that α-CYP binds to HDAC-2 with good affinity, ascertained by molecular dynamics simulations and binding free energy analysis. Overall, our data suggest that α-CYP can effectively prevent renal injury in diabetic rats by regulating oxidative stress, tissue inflammation, fibrosis and inhibiting HDAC-2 activity.