“…PDTC suppresses the role of NF-κB by inhibiting IκBα phosphorylation. 26 , 27 In HK2 cells, PDTC inhibited the decrease in PGC-1 α protein levels induced by rhTWEAK treatment ( Figure 7B ), indicating that the canonical NF-κB pathway participated in the mediation of the TWEAK-induced downregulation of PGC-1α expression. Figure 7 PDTC attenuated TWEAK regulation of PGC-1α expression.…”
Purpose
Current studies on the mechanism of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis (LN) mainly focus on the inflammatory pathway. Herein, we aimed to determine whether TWEAK could promote the progression of renal interstitial fibrosis by regulating peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) expression and intervening in lipid metabolism in LN.
Materials and Methods
MRL/lpr mice, an animal model of lupus, were treated with the anti-TWEAK antibody or co-treated with adeno-associated virus-mediated PGC-1α short hairpin RNA (shRNA). In addition, human proximal tubular epithelial cells (HK2 cells) were treated with recombinant human TWEAK (rhTWEAK) or ammonium pyrrolidine dithiocarbamate (PDTC) in vitro.
Results
The renal contents of free fatty acids and triglycerides were higher in MRL/lpr mice than in MRL/MpJ mice; however, these contents were decreased by treatment with the anti-TWEAK antibody. Based on immunofluorescence staining, the expression of PGC-1α was markedly more in the renal tubules of MRL/MpJ mice than in the glomeruli. However, treatment with anti-TWEAK antibody increased the levels of PGC-1α and its downstream target genes, which were remarkably lower in MRL/lpr mice than in MRL/MpJ mice. Anti-TWEAK antibody effectively eased renal interstitial fibrosis, which manifested as a decrease in the deposition of collagen fibers and the inhibition of type I collagen and fibronectin expression. However, the therapeutic effects of the anti-TWEAK antibody were abolished by PGC-1α shRNA. Treatment with rhTWEAK decreased PGC-1α expression in both dose- and time-dependent manners in HK2 cells in vitro. PDTC, an inhibitor of IκBα phosphorylation, suppressed the decrease in the PGC-1α protein level induced by rhTWEAK treatment.
Conclusion
Our results suggest that TWEAK prevents renal tubular PGC-1α expression by promoting NF-κB activation, resulting in a deficiency in lipid metabolism and the progress of renal interstitial fibrosis. The upregulation of renal tubular PGC-1α expression to improve lipid metabolism is one of the mechanisms employed by the anti-TWEAK antibody to treat renal interstitial fibrosis.
“…PDTC suppresses the role of NF-κB by inhibiting IκBα phosphorylation. 26 , 27 In HK2 cells, PDTC inhibited the decrease in PGC-1 α protein levels induced by rhTWEAK treatment ( Figure 7B ), indicating that the canonical NF-κB pathway participated in the mediation of the TWEAK-induced downregulation of PGC-1α expression. Figure 7 PDTC attenuated TWEAK regulation of PGC-1α expression.…”
Purpose
Current studies on the mechanism of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis (LN) mainly focus on the inflammatory pathway. Herein, we aimed to determine whether TWEAK could promote the progression of renal interstitial fibrosis by regulating peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) expression and intervening in lipid metabolism in LN.
Materials and Methods
MRL/lpr mice, an animal model of lupus, were treated with the anti-TWEAK antibody or co-treated with adeno-associated virus-mediated PGC-1α short hairpin RNA (shRNA). In addition, human proximal tubular epithelial cells (HK2 cells) were treated with recombinant human TWEAK (rhTWEAK) or ammonium pyrrolidine dithiocarbamate (PDTC) in vitro.
Results
The renal contents of free fatty acids and triglycerides were higher in MRL/lpr mice than in MRL/MpJ mice; however, these contents were decreased by treatment with the anti-TWEAK antibody. Based on immunofluorescence staining, the expression of PGC-1α was markedly more in the renal tubules of MRL/MpJ mice than in the glomeruli. However, treatment with anti-TWEAK antibody increased the levels of PGC-1α and its downstream target genes, which were remarkably lower in MRL/lpr mice than in MRL/MpJ mice. Anti-TWEAK antibody effectively eased renal interstitial fibrosis, which manifested as a decrease in the deposition of collagen fibers and the inhibition of type I collagen and fibronectin expression. However, the therapeutic effects of the anti-TWEAK antibody were abolished by PGC-1α shRNA. Treatment with rhTWEAK decreased PGC-1α expression in both dose- and time-dependent manners in HK2 cells in vitro. PDTC, an inhibitor of IκBα phosphorylation, suppressed the decrease in the PGC-1α protein level induced by rhTWEAK treatment.
Conclusion
Our results suggest that TWEAK prevents renal tubular PGC-1α expression by promoting NF-κB activation, resulting in a deficiency in lipid metabolism and the progress of renal interstitial fibrosis. The upregulation of renal tubular PGC-1α expression to improve lipid metabolism is one of the mechanisms employed by the anti-TWEAK antibody to treat renal interstitial fibrosis.
“…Previous studies have demonstrated that CYP1A1 expression is induced depending on the expression level of aryl hydrocarbon receptor in the NASH model and that treatment of HepG2 cells with oleic acid accelerates lipid peroxidation (Xia et al, 2019). In addition, CYP1A1 expression is induced by LPS-induced NF-κB activation, which contributes to lung tissue damage and inflammation (Tian et al, 2020). In contrast, the CYP4A family contributes to the ω hydroxylation of saturated straight-chain fatty acids (Johnston et al, 2011;Choi et al, 2018).…”
Clarifying the cytochrome P450s (CYPs) changes in non-alcoholic fatty liver disease (NAFLD) is important for optimizing drug therapy. This study compared the expression of CYP isoforms in rat models of nonalcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). An NAFL model without tissue damage or inflammation was established by feeding rats a high-fat diet (HFD) for a relatively short period of 4 weeks. Feeding rats with a methionine-choline-deficient diet (MCDD) for 4 weeks produced steatohepatitis-like NASH. Here, the mRNA and protein expression levels of several CYP enzymes in NAFL and NASH models were compared with those in rats fed a control diet (CD). CYP1A2 expression and activity were upregulated in the NAFL model and downregulated in the NASH model, suggesting a reversal of CYP1A2 expression between NAFL and NASH. Differential expression of CYP1A2 in the NAFL and NASH models was observed in primary rat hepatocytes. These findings suggest that CYP1A2 expression/activity vary from the early stages of NAFL to NASH and that monitoring the pharmacokinetics of CYP1A2-metabolized drugs in humans with NAFL and NASH is necessary.
“…During ALI, various oxidases are activated through different pathways, contributing to oxidative stress. These oxidases include NO synthase (NOS) [165], Xanthine oxidase (XO) [166] and Cytochrome P450 (CYP) [167]. Since many oxidases are present in endothelial mitochondria, and mitochondria are the primary site of REDOX reactions, oxidative stress can lead to mitochondrial damage.…”
Sepsis, a prevalent critical condition in clinics, continues to be the leading cause of death from infections and a global healthcare issue. Among the organs susceptible to the harmful effects of sepsis, the lungs are notably the most frequently affected. Consequently, patients with sepsis are predisposed to developing acute lung injury (ALI), and in severe cases, acute respiratory distress syndrome (ARDS). Nevertheless, the precise mechanisms associated with the onset of ALI/ARDS remain elusive. In recent years, there has been a growing emphasis on the role of endothelial cells (ECs), a cell type integral to lung barrier function, and their interactions with various stromal cells in sepsis-induced ALI/ARDS. In this comprehensive review, we summarize the involvement of endothelial cells and their intricate interplay with immune cells and stromal cells, including pulmonary epithelial cells and fibroblasts, in the pathogenesis of sepsis-induced ALI/ARDS, with particular emphasis placed on discussing the several pivotal pathways implicated in this process. Furthermore, we discuss the potential therapeutic interventions for modulating the functions of endothelial cells, their interactions with immune cells and stromal cells, and relevant pathways associated with ALI/ARDS to present a potential therapeutic strategy for managing sepsis and sepsis-induced ALI/ARDS.
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