Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation

Abstract

Glomerulosclerosis and interstitial fibrosis represent the key events in development of diabetic nephropathy (DN), with connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and fibronectin 1 (FN-1) playing important roles in these pathogenic processes. To investigate whether the plant metabolite curcumin, which exerts epigenetic modulatory properties when applied as a pharmacologic agent, may prevent DN via inhibition of the JNK pathway and epigenetic histone acetylation, diabetic and age-matched non-diabetic control mice were administered a 3-month course of curcumin analogue (C66), c-Jun N-terminal kinase inhibitor (JNKi, sp600125), or vehicle alone. At treatment end, half of the mice were sacrificed for analysis and the other half were maintained without treatment for an additional 3 months. Renal JNK phosphorylation was found to be significantly increased in the vehicle-treated diabetic mice, but not the C66- and JNKi-treated diabetic mice, at both the 3-month and 6-month time points. C66 and JNKi treatment also significantly prevented diabetes-induced renal fibrosis and dysfunction. Diabetes-related increases in histone acetylation, histone acetyl transferases’ (HATs) activity, and the p300/CBP HAT expression were also significantly attenuated by C66 or JNKi treatment. Chromatin immunoprecipitation assays showed that C66 and JNKi treatments decreased H3-lysine9/14-acetylation (H3K9/14Ac) level and p300/CBP occupancy at the CTGF, PAI-1 and FN-1 gene promoters. Thus, C66 may significantly and persistently prevent renal injury and dysfunction in diabetic mice via down-regulation of diabetes-related JNK activation and consequent suppression of the diabetes-related increases in HAT activity, p300/CBP expression, and histone acetylation.

Danshen injection ameliorates STZ-induced diabetic nephropathy in association with suppression of oxidative stress, pro-inflammatory factors and fibrosis

“…4B). Furthermore, density of cells with expression of fibronectin, a major profibrotic cytokine that plays an important role in fibrotic processes [22], was found increased in diabetes group (P b 0.01, compared with control group, Fig. 4C and D) but alleviated upon Danshen injection.…”

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

“…As described in our previous study (25), EpiQuik™ Tissue ChIP Kit (P-2012; Epigentek Group Inc., Farmingdale, NY, USA) was used to perform the ChIP assay according to the manufacturer's protocol. In brief, the acetylated histone H3 antibody (1 µg, Epigentek Group Inc.) or 1 µl of normal mouse IgG (as a negative control) was used to pre-coat the assay wells.…”

Epigenetic regulation of cardiac fibrosis

“…In a model of diabetic renal fibrosis induced by streptozotocin (STZ), C66, a curcumin analog, blocked glomerular and interstitial fibrosis, which was associated with reduced renal mitogen activated protein kinase (MAPK) signaling [53, 54]. Chromatin immunoprecipitation (ChIP) revealed that C66 reduced STZ-mediated recruitment of p300 to the promoters for the genes encoding CTGF, PAI-1 and fibronectin, and this was associated with reduced H3K9/14 acetylation at these sites.…”