Activated Histone Acetyltransferase p300/CBP-Related Signalling Pathways Mediate Up-Regulation of NADPH Oxidase, Inflammation, and Fibrosis in Diabetic Kidney

Abstract

Accumulating evidence implicates the histone acetylation-based epigenetic mechanisms in the pathoetiology of diabetes-associated micro-/macrovascular complications. Diabetic kidney disease (DKD) is a progressive chronic inflammatory microvascular disorder ultimately leading to glomerulosclerosis and kidney failure. We hypothesized that histone acetyltransferase p300/CBP may be involved in mediating diabetes-accelerated renal damage. In this study, we aimed at investigating the potential role of p300/CBP in the up-regulation of renal NADPH oxidase (Nox), reactive oxygen species (ROS) production, inflammation, and fibrosis in diabetic mice. Diabetic C57BL/6J mice were randomized to receive 10 mg/kg C646, a selective p300/CBP inhibitor, or its vehicle for 4 weeks. We found that in the kidney of C646-treated diabetic mice, the level of H3K27ac, an epigenetic mark of active gene expression, was significantly reduced. Pharmacological inhibition of p300/CBP significantly down-regulated the diabetes-induced enhanced expression of Nox subtypes, pro-inflammatory, and pro-fibrotic molecules in the kidney of mice, and the glomerular ROS overproduction. Our study provides evidence that the activation of p300/CBP enhances ROS production, potentially generated by up-regulated Nox, inflammation, and the production of extracellular matrix proteins in the diabetic kidney. The data suggest that p300/CBP-pharmacological inhibitors may be attractive tools to modulate diabetes-associated pathological processes to efficiently reduce the burden of DKD.

Preclinical Studies of Natural Products Targeting the Gut Microbiota: Beneficial Effects on Diabetes

“…Diabetes mellitus (DM) is one of the most common chronic diseases and causes life-threatening complications in multiple organs, making it a global health challenge. − According to statistics, the number of diabetics in the world was 460 million in 2019, which will increase to 570 million and 700 million by 2030 and 2045, respectively . DM is mainly divided into type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), and more than 90% of DM patients are diagnosed with T2DM .…”

Kidney fibrosis: from mechanisms to therapeutic medicines

“…193,194 The HATs mainly included the P300/CREB binding protein (CBP) and P300/CBP-associated factor (PCAF). P300 inhibitors, L002, 195 C646, 196,197 and C66 198 reduced renal fibrosis in the hypertensive and diabetic kidneys. Garcinol, a PACF inhibitor, alleviated kidney fibrosis of UUO model by inhibiting the activation of NF-κB and NRF2.…”

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs

“…The treatment of human cardiac fibroblasts with C646 blocks TGFβ-induced collagen synthesis [86]. In SIRT3-KO mice with coronary microvascular dysfunction models, C646 alleviated cardiac remodeling, including cardiac fibrosis, hypertrophy, and capillary rarefaction [89]. On streptozotocin-induced diabetic C57BL/6J mice, C646 down-regulated diabetes-induced pro-fibrotic molecules such as collagen IV, fibronectin, and laminin and significantly reduced diabetes-induced glomerular hypertrophy derived from the accumulation of the ECM proteins [90].…”