Curcumin protects renal tubular epithelial cells from high glucose-induced epithelial-to-mesenchymal transition through Nrf2-mediated upregulation of heme oxygenase-1

Abstract

Curcumin has been observed to exhibit an anti-fibrotic effect in the liver, lung and gallbladder. However, the mechanisms underlying the cytoprotective effects of curcumin remain to be elucidated. The epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in the kidney is considered to contribute to the renal accumulation of matrix proteins associated with diabetic nephropathy. The EMT is also closely associated with the progression of renal interstitial fibrosis and oxidative stress. This process may occur through abrogation of high glucose (HG)-induced oxidative stress via activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in kidney tubular epithelial cells. In the present study, the effect of curcumin on HG-induced EMT in the NRK-52E normal rat kidney tubular epithelial cell line was investigated, and whether the effect of curcumin was mediated by the induction of Nrf2 and HO-1 expression was examined. The present study revealed that curcumin was able to prevent events associated with EMT, including the downregulation of E-cadherin and the increased expression of α-smooth muscle actin. Further analysis revealed that the expression levels of Nrf2 and HO-1 protein were elevated to a greater extent in the curcumin pretreated NRK-52E cells compared with those of the control. Notably, knockdown of Nrf2 with small interfering RNA prevented the curcumin-induced elevation in expression of HO-1 and the associated anti-fibrotic effects. In conclusion, the present findings suggested that curcumin may be significant in cellular antioxidant defense, through the activation of Nrf2 and HO-1, thereby protecting the NRK-52E cells from HG-induced EMT.

Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis

“…This is corroborated by our findings that lung fibrotic responses to BLM were more severe and earlier in Nrf2 −/− mice compared to WT mice. Although Nrf2–antioxidant system was involved in TGF-β1-induced EMT during renal fibrosis, there are no direct evidences regarding the relationship between Nrf2 and EMT during PF15202122. In the present study, EMT markers were more obvious accompanied by the loss of epithelial marker E-cadherin as well as the increase of vimentin and α-SMA in Nrf2 −/− mice compared to WT mice.…”

Natural Nrf2 activators in diabetes

“…In normal rat kidney tubular epithelial cells incubated with high glucose concentrations, curcumin elevated the protein levels of Nrf2 and heme oxygenase-1 (HO-1) that promoted the antifibrotic effects [108]. In rats with experimental diabetic nephropathy induced by STZ, curcumin restores renal integrity by normalizing levels of glutathione (GSH), the activity of SOD, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, aldose reductase, sorbitol dehydrogenase and the ratio of fatty acids in membrane such as polyunsaturated and saturated fatty acids [109].…”

Tempol effect on epithelial-mesenchymal transition induced by hyperglycemia

“…On the other hand, EMT has been known as a common finding in kidney injury, including DN (16). Therefore, a couple of studies have been allocated to figure out if antioxidant agents, can modify kidney injury in diabetic milieu (17).…”