Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice

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.

FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner

“…We demonstrate by ChIP that FOXC2 binds to its promoter and its binding affinity is enhanced by LPS treatment. Our data also reveal that garcinol, a HAT inhibitor, that is specific to p300 and PCAF (Balasubramanyam et al, 2004;Kim et al, 2020;Wang et al, 2020;Kopytko et al, 2021), represses LPS-stimulated histone acetylation at FOXC2 promoter, FOXC2 binding affinity and FOXC2 expression in HPMEC-Im. Our data shows that LPS-stimulated FOXC2 expression in primary HPMEC is also repressed by garcinol consistent with our data in immortalized HPMEC.…”

Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

“…Immunohistochemical staining for 4-hydroxynonenal (4-HNE)—a major product of lipid peroxidation [ 18 ]—revealed that the percentage of the 4-HNE-stained area was increased after DDC feeding ( Figure 2 C,D). Hepatic levels of malondialdehyde (MDA)—another marker of lipid peroxidation [ 19 ]—were also increased ( Figure 2 E). However, the DDC-diet-induced oxidative stress was significantly suppressed by CoPP ( Figure 2 A–E).…”

Mechanism Prediction of Astragalus membranaceus against Cisplatin-Induced Kidney Damage by Network Pharmacology and Molecular Docking

“…The targets are mainly associated with oxidative stress, apoptosis, inflammation, and cell proliferation. According to quantities of studies, apoptosis induced by TNF- α , p53, and caspase-3 [ 43 , 44 ] and inflammation induced by IL-6, TNF- α , and interleukin-1 beta (IL-1 β ) played an essential role in cisplatin-induced kidney damage [ 45 , 46 ]. It was reported that cisplatin increased the expression of proinflammatory cytokine TNF- α , which induced an exogenous apoptotic pathway through its tumor necrosis factor receptor 1 (TNFR1) [ 47 ], and TNF- α can activate proinflammatory cytokines and chemokines such as NF- κ B and trigger oxidative stress, which ultimately aggravates kidney damage [ 48 ].…”