Curcumin attenuates cyclosporine A‑induced renal fibrosis by inhibiting hypermethylation of the klotho promoter.

Abstract

Chronic kidney disease is increasingly considered to be a worldwide public health problem and usually leads to renal fibrosis. In the present study, curcumin, a polyphenol pigment extracted from turmeric, was demonstrated to exert protective effects on renal fibrosis via the suppression of transforming growth factor‑β (TGF‑β) downstream signaling, such as plasminogen activator inhibitor‑1 (PAI‑1), α‑smooth muscle actin (α‑SMA) and collagenI (ColI) downregulation. The present findings demonstrate that curcumin exerted a protective effect on cyclosporineA‑induced renal fibrosis via a klotho (KL)‑dependent mechanism, which inhibits the TGF‑β signaling pathway. Further research indicated that curcumin induced KL expression in HK‑2 tubular epithelial cells by inhibiting CpG hypermethylation in the KL promoter, which mediates the loss of expression in cells. Methylation‑specific polymerase chain reaction (PCR) combined with bisulfite sequencing identified numerous key CpG sites, such as 249, 240 and 236, whose methylation statuses are important for KL expression. A PCR reporter assay was utilized to further confirm these findings. In addition, the effects of curcumin on the regulation of DNA methyltransferase1 (Dnmt1) expression were evaluated, and the data suggest that curcumin inhibits Dnmt1 expression and restricts CpG hypermethylation. Thus, the current study reveals that curcumin attenuated renal fibrosis by suppressing CpG methylation in the KL promoter, thus inducing KL expression, which inhibited TGF‑β signaling, which may provide a novel therapeutic approach for the treatment of renal fibrosis.