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 collagen I (Col I) downregulation. The present findings demonstrate that curcumin exerted a protective effect on cyclosporine A‑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 methyltransferase 1 (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.

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

“…The decrease in Klotho transcription in kidney disease has been attributed to regulation by NF-κB or Angiotensin II or more recently to modifications of Klotho promoter acetylation 23 or methylation. [62][63][64] We observed an induction of ATF3 by proteinuria in different models, both in proximal and distal tubular segments. Recently, it was demonstrated by chromatin immunoprecipitation that ATF3 binds to the Klotho promoter as a heterodimer with c-Jun.…”

Protective effect of curcumin against cyclosporine A‑induced rat nephrotoxicity

“…Tirkey et al (42) reported that, through its antioxidant activity, Cur effectively salvaged CsA-induced nephrotoxicity. Furthermore, Hu et al (43) demonstrated that the protective effect of Cur may be mediated by inhibiting the hypermethylation of the klotho promoter. The present study confirmed that Cur significantly increased renal antioxidant capacity and decreased the Bax/Bcl-2 ratio in CsA-treated HK-2 cells, which may be associated with the improvements in CsA-induced renal failure and renal tubular deformation and cell vacuolization following Cur treatment in rats.…”

Curcumin suppresses cardiac fibroblasts activities by regulating the proliferation and cell cycle via the inhibition of the p38 MAPK/ERK signaling pathway

“…Curcumin (diferuloylmethane) has been reported to exhibit several beneficial properties, including anti-inflammatory, anti-oxidative, anti-proliferative, and anti-apoptotic activities ( 6 ). Accumulating evidence has demonstrated preventive effects of curcumin in fibrotic diseases, including oral submucosal ( 7 ), liver ( 8 ), lung ( 9 ), and kidney fibrosis ( 10 ). In a previous study, the cardiac protective effect of curcumin was demonstrated in several heart diseases, such as hypertension, myocardial infarction, and diabetic cardiomyopathy ( 11 – 13 ).…”