Salidroside alleviates high glucose-induced oxidative stress and extracellular matrix accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway.

Diabetic nephropathy (DN) is a metabolic disease characterized by mesangial cell proliferation and extracellular matrix (ECM) accumulation. Salidroside (SAL) is the major ingredient in Rhodiola rosea and possesses beneficial effects on DN. This study aimed to evaluate the effect of SAL on high glucose (HG)-induced oxidative stress and ECM accumulation and the underlying mechanism. Rat glomerular mesangial cells HBZY-1 were induced by high glucose (HG) in the presence or absence of SAL. Cell proliferation was measured by CCK-8 assay. The reactive oxygen species (ROS) level, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected to evaluate oxidative stress. The expression levels of ECM proteins including fibronectin (FN) and type IV collagen (Coll IV) were detected by qRT-PCR and western blot analysis. The expressions of thioredoxin-interacting protein (TXNIP), nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 were assessed by western blot. Si-TXNIP or si-NC was transfected into HBZY-1 cells to inhibit TXNIP-NLRP3 inflammasome pathway. The results showed that SAL treatment alleviated HG-induced cell proliferation. SAL reduced the levels of ROS and MDA, and induced the SOD activity. Besides, the mRNA and protein expressions of FN and Coll IV were decreased by SAL. The expression levels of TXNIP, NLRP3, ASC, and caspase-1 were reduced in the SAL treated cells. In addition, TXNIP knockdown inhibited TXNIP-NLRP3 inflammasome activation and suppressed HG-induced cell proliferation, oxidative stress, and ECM accumulation. In conclusion, SAL alleviated HG-induced oxidative stress and ECM accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway.

Wang S ，Zhao X ，Yang S ，Chen B ，Shi J ... -  《-》

Artesunate ameliorates high glucose-induced rat glomerular mesangial cell injury by suppressing the TLR4/NF-κB/NLRP3 inflammasome pathway.

Inflammatory response is important for the development and progression of diabetic nephropathy (DN). Artesunate (ART), an antimalarial drug, possesses anti-inflammatory effect and exhibits protective effect on chronic kidney diseases. However, the effect of ART on DN is unknown. The aim of the present study was to evaluate the effect and the molecular mechanism of ART on DN in an in vitro model. The rat mesangial cell line, HBZY-1, was induced by high glucose (HG; 30 mM d-glucose) in the presence or absence of ART (15 and 30 μg/ml) and incubated for 24 h. We found that HG induced the proliferation of HBZY-1 cells, while treatment with ART inhibited the cell proliferation. Treatment with ART inhibited HG-induced inflammatory cytokines production and expression of extracellular matrix (ECM). Besides, HG induced reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and inhibited the superoxide dismutase (SOD) activity of HBZY-1 cells, and the effects were attenuated by ART treatment. ART decreased HG-induced the expression levels of toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), nuclear factor κB (NF-κB) p-p65, and nod-like receptor protein 3 (NLRP3). Inhibition of the TLR4/NF-κB pathway suppressed NLRP3 inflammasome in HBZY-1 cells. In conclusion, ART exhibited protective effect on HG-induced HBZY-1 cells by inhibiting the inflammatory response, oxidative stress and ECM accumulation. The TLR4/NF-κB/NLRP3 inflammasome pathway was involved in the protective effect of ART. The results suggested that ART might be a potential therapy agent for the DN treatment.

Sun Z ，Ma Y ，Chen F ，Wang S ，Chen B ，Shi J ... -  《-》

Liquiritigenin attenuates high glucose-induced mesangial matrix accumulation, oxidative stress, and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways.

Oxidative stress, inflammation, and hyperglycemia are considered to play crucial roles in the pathogenesis and progression of diabetic nephropathy (DN). Liquiritigenin, one of the flavonoid compounds, has been shown to possess anti-inflammatory, anti-hyperlipidemic, and anti-oxidative properties. Our study aimed to explore the effects of liquiritigenin on high glucose (HG)-induced extracellular matrix (ECM) accumulation, oxidative stress and inflammatory response and delineate the underlying mechanism. In our study, glomerular mesangial cells (HBZY-1) were co-treated with various doses of liquiritigenin and HG. We found that HG, but not normal glucose or mannitol, promoted the proliferation of HBZY-1 cells, which was suppressed by liquiritigenin. Liquiritigenin inhibited HG-induced ECM accumulation in HBZY-1 cells by reducing the expressions and production of collagen IV (Col IV) and fibronectin (FN). Moreover, liquiritigenin attenuated HG-induced oxidative stress, as evidenced by the decreased MDA content and NADPH oxidase 4 (NOX4) expression, and the increased SOD activity in HBZY-1 cells. Liquiritigenin suppressed HG-induced inflammatory response, as demonstrated by the reduced expressions and secretion of interleukin (IL)-6 and IL-1β in HBZY-1 cells. Furthermore, we found that liquiritigenin inhibited HG-induced activation the nuclear factor-kappa B (NF-κB) and nod-like receptor protein 3 (NLRP3) inflammasome pathways. In conclusion, these results demonstrated that liquiritigenin attenuated HG-induced ECM accumulation, oxidative stress, and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways, suggesting that liquiritigenin might be a promising therapeutic agent for preventing the development of DN.

Zhu X ，Shi J ，Li H 《-》

Tangeretin inhibits high glucose-induced extracellular matrix accumulation in human glomerular mesangial cells.

Tangeretin (5, 6, 7, 8, 4'-pentamethoxyflavone), a natural compound extracted from citrus plants, has been shown to possess a variety of pharmacological activities, including anti-oxidant, anti-tumor, cytostatic and anti-diabetic properties. However, the role of tangeretin in diabetic nephropathy (DN) has not yet been investigated. This study was undertaken to elucidate the effects of tangeretin on high glucose (HG)-induced oxidative stress and extracellular matrix (ECM) accumulation in human glomerular mesangial cells (MCs) and explore the underlying mechanisms. Our results showed that tangeretin significantly inhibited HG-induced the proliferation of MCs. In addition, tangeretin dramatically reduced the levels of reactive oxygen species (ROS) and malondialdhyde (MDA), and induced SOD activity, as well as inhibited the expression of fibronectin (FN) and collagen IV in HG-stimulated MCs. Furthermore, tangeretin efficiently prevented the activation of ERK signaling pathway in HG-stimulated MCs. Taken together, these data indicated that tangeretin inhibits HG-induced cell proliferation, oxidative stress and ECM expression in glomerular MCs, at least in part, through the inactivation of ERK signaling pathway. Therefore, tangeretin may be a potential agent in the treatment of DN.

Chen F ，Ma Y ，Sun Z ，Zhu X ... -  《-》

Reactive oxygen species-induced TXNIP drives fructose-mediated hepatic inflammation and lipid accumulation through NLRP3 inflammasome activation.

Zhang X ，Zhang JH ，Chen XY ，Hu QH ，Wang MX ，Jin R ，Zhang QY ，Wang W ，Wang R ，Kang LL ，Li JS ，Li M ，Pan Y ，Huang JJ ，Kong LD ... -  《-》