Abstract
Diabetic nephropathy is a microvascular complication induced by diabetes, and methylglyoxal (MGO) is a reactive carbonyl species causing oxidative stress that contributes to the induction of inflammatory response in kidney cells. Cudrania tricuspidata (CT), cultivated in Northeast Asia, has been used as traditional medicine for treating various diseases, including neuritis, liver damage, and cancer. In this study, we determined whether a CT root extract (CTRE) can prevent MGO-induced reactive oxygen species (ROS) production and inflammation and assessed underlying mechanisms using a kidney epithelial cell line, HK-2. We observed that CTRE inhibited MGO-induced ROS production. Additionally, CTRE ameliorated the activation of MGO-induced inflammatory signaling pathways such as p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and c-JUN N-terminal kinase (JNK). Consistent with these results, expressions of p-nuclear factor-kappa B (NFκB) and inflammatory cytokines, tumor necrosis factor-α, interleukin- (IL-) 1β, and IL-6, were decreased when compared with MGO-only exposed HK-2 cells. CTRE alleviated the MGO-induced decrease in nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and antioxidant enzyme mRNA expressions. MGO induced the expression of NADPH oxidase 4 (NOX4); CTRE pretreatment inhibited this induction. Further studies revealed that the NOX4 expression was inhibited owing to the suppression of MGO-induced protein kinase C (PKC) activation following CTRE treatment. Collectively, our data suggest that CTRE attenuates MGO-induced inflammation and oxidative stress via inhibition of PKC activation and NOX4 expression, as well as upregulating the Nrf2-antioxidant enzyme pathway in HK-2 cells.
Highlights
Diabetic nephropathy (DN) is one of the most important and common complications of diabetes [1]
To determine whether CT root extract (CTRE) has cytotoxic effects on HK-2 cells, we examined the viability of HK-2 cells after treatment with different concentrations of CTRE
These results indicate that the CTRE concentrations used in this study did not demonstrate any cellular toxicity in HK-2 cells
Summary
Diabetic nephropathy (DN) is one of the most important and common complications of diabetes [1]. MGO accumulation has been implicated in vascular complications of diabetes and chronic inflammatory diseases, including cardiovascular disease, cancer, cognitive dysfunction, and bone loss [4,5,6,7,8,9,10]. It has been used as a traditional medicine for tumors, liver damage, jaundice, contusions, chronic gastritis, rheumatism, neuritis, and inflammation in East Asia [11, 12]. The roots, stems, leaves, and fruits of CT reportedly contain large amounts of phenolic compounds, including flavonoids, xanthones, diterpenoids, alkaloids, and terpenoids [12,13,14]. We investigated the effect of the CT root extract (CTRE) on MGO-induced ROS production and expression of inflammatory cytokines in HK-2 cells, a human tubular epithelial cell line, and assessed the underlying molecular mechanisms
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