Abstract
4-Hydroxy-2-hexenal (HHE), the aldehyde product of lipid peroxidation, may be responsible for the pathogenesis of progressive renal disease. Recently, paricalcitol (19-nor-1,25-dihydroxyvitamin D2) was shown to be renoprotective through its anti-inflammatory and antifibrotic effects in various experimental nephropathy models. In this study, we investigated the effects of paricalcitol on inflammation and epithelial-mesenchymal transition (EMT) after HHE-induced renal tubular epithelial cell injury. To investigate the molecular mechanisms underlying HHE-induced renal tubular cell injury, the human proximal tubular epithelial (HK-2) cells cultured with 10 µM HHE in the presence or absence of paricalcitol. In HK-2 cells, paricalcitol attenuated the HHE-induced expression of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, and prevented nuclear factor-κB (NF-κB) activation. The expression of the inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2 was attenuated by paricalcitol pretreatment. In addition, HHE increased the expression of the transforming growth factor (TGF)-β/Smad signaling proteins and fibrotic proteins, such as α-smooth muscle actin and connective tissue growth factor; this inducible expression was suppressed by pretreatment with paricalcitol. Treatment with HHE resulted in the activation of the β-catenin signaling pathway, and paricalcitol pretreatment reduced the expression of β-catenin in HHE-treated HK-2 cells. Coimmunoprecipitation shows that paricalcitol induced vitamin D receptor (VDR)/β-catenin complex formation in HK-2 cells. Also immunofluorescence staining revealed that co-localization of VDR and β-catenin in the nuclei. ICG-001, an inhibitor of β-catenin, decreased the expression of TGF-β1 and attenuated HHE-induced tubular EMT. These results show that paricalcitol attenuated HHE-induced renal tubular cell injury by suppressing inflammation and EMT process through inhibition of the NF-κB, TGF-β/Smad, and β-catenin signaling pathways.
Highlights
Oxidative stress, which can often result in tissue damage, is defined as an imbalance between an excessive generation of oxidant compounds and insufficient antioxidant defense mechanisms
Our more recent study demonstrated that HHE, an aldehyde product of lipid peroxidation, induces apoptosis through reactive oxygen species (ROS)-mediated activation of the nuclear factor-kB (NF-kB) pathway in human proximal epithelial (HK-2) cells [7]
We investigated the molecular mechanisms of inflammatory response and epithelial-mesenchymal transition (EMT) and determined whether paricalcitol has anti-inflammatory and anti-fibrotic effects in HK-2 cells treated with HHE
Summary
Oxidative stress, which can often result in tissue damage, is defined as an imbalance between an excessive generation of oxidant compounds and insufficient antioxidant defense mechanisms. Malondialdehyde has been considered as the major deleterious lipid peroxidation byproduct, much of the current work on the toxicity of lipid peroxidation byproducts focuses on the more reactive hydroxyalkenals, such as 4-hydroxy-2-nonenal and 4-hydroxy-2-hexenal (HHE). These products are readily generated in vivo following application of various biological/biochemical insults [1]. Increased ROS has been shown to be associated with kidney fibrosis, promoting the production of collagen, fibronectin, and a-smooth muscle actin (SMA) [8], and to play a pivotal role in inflammation through the NF-kB pathway [9] It remains largely unknown whether lipid-derived aldehydes induce inflammatory responses and epithelial-mesenchymal transition (EMT) in tubular epithelial cells
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