Abstract
Emerging evidence suggests that epigenetic mechanisms such as histone modification are crucially involved in the pathophysiology of acute kidney injury (AKI). The histone acetyltransferase p300 regulates several biological processes through the acetylation of histones or transcription factors. However, the role of p300 in cisplatin-induced AKI remains poorly understood. Therefore, we investigated the effects of garcinol, a potent p300 inhibitor, on cisplatin-induced AKI and explored the mechanisms. Administration of garcinol significantly reversed the upregulation of p300 and increased acetylation of histone H3, along with amelioration of renal dysfunction and histopathological injury in the kidneys of cisplatin-injected mice. Garcinol also attenuated oxidative stress and reduced expression of pro-oxidant enzymes. In addition, garcinol reduced the elevated production of cytokines and chemokines and suppressed immune cell accumulation together with downregulation of vascular adhesion molecules. These beneficial effects of garcinol were associated with a reduction in acetylation of the p65 subunit of nuclear factor kappa-B. Further, garcinol significantly inhibited apoptosis and caspase-3 activation, with a decrease in p53 acetylation in cisplatin-injected mice. Taken together, we demonstrated that the inhibition of p300 by garcinol ameliorated cisplatin-induced renal injury, presumably through epigenetic mechanisms. These results suggest that garcinol might be a potential preventive agent for cisplatin-induced AKI.