Parthenolide regulates DNMT1-mediated methylation of VDR promoter to relieve podocyte damage in mice with diabetic nephropathy

Abstract

Current evidence showed that parthenolide (PN) has strong anti-inflammatory activity, but its effect on diabetic nephropathy (DN) is still unclear. In this research, high glucose (HG)-induced MPC5 cells were incubated with 5, 10 or 20 μM PN, and we found that PN incubation improved HG-induced MPC5 cells viability and apoptosis, ROS level, LDH activity and the secretion of inflammatory factors (IL-6, TNF-α and IL-1β), and inhibited the expression of DNMT1 protein, and promoted the expression of VDR, p-AKT, nephrin and podocin proteins. Lentivirus-mediated VDR overexpression vector (LV-VDR) transfection had the same effect, and LV-DNMT1 or si-VDR transfection or 100 nM AKT inhibitor MK2206 incubation reversed the effect of PN on cell functions. Research on the mechanism found that PN reduced the level of VDR methylation by reducing the enrichment of DNTM1 in the VDR promoter region under high glucose condition. In vivo, C57BL/6 mice were injected with streptozotocin (STZ) intraperitoneally to construct a DN mouse model, and 5mg/kg PN was administered intraperitoneally every other day. The results showed that PN treatment improved glomerular hypertrophy and renal fibrosis in STZ-induced mice. In general, PN regulated DNTM1-mediated VDR methylation, activated AKT, and alleviated DN.

The antioxidant activity of Chuju polysaccharide and its effects on the viscera of diabetic mice

“…Physiological characteristics are glucose intolerance, obesity, hypertension and premature atherosclerosis (Muche et al, 2020). Damage to other organs is manifested as acute pancreatitis, diabetic nephropathy, diabetic peripheral neuropathy, such as insulin resistance, hypertension and dyslipidemia (Yang et al, 2022a). These changes are also associated with oxidative (Krycer et al, 2020).…”

Modulation of the vitamin D receptor by traditional Chinese medicines and bioactive compounds: potential therapeutic applications in VDR-dependent diseases

“…In a cellular context, parthenolide significantly improved high glucose-induced apoptosis and inflammation in MPC5 cells, a podocyte cell line. It was also observed to increase the expression levels of matrix-related proteins such as nephrin and podocin, key elements in maintaining podocyte integrity ( Yan et al, 2022 ).…”

“…Parthenolide has shown potential as a DNA methylation inhibitor—it was observed to inhibit DNA methyltransferase 1 (DNMT1) ( Liu et al, 2009 ), a noteworthy effect considering DNMT1 was found to be upregulated in diabetic nephropathy mice and high glucose-induced MPC5 cells ( Yan et al, 2022 ). This upregulation contributes to the hypermethylation of the VDR gene, which is significantly associated with lower VDR gene expression levels and vitamin D levels ( Guan et al, 2022 ).…”