Andrographolide ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated renal oxidative stress and inflammation via Akt/NF-κB pathway.

Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial hypertrophy and extracellular matrix (ECM) accumulation. Our recent study found that andrographolide inhibited high glucose-induced mesangial cell proliferation and fibronectin expression through inhibition of AP-1 pathway. However, whether andrographolide has reno-protective roles in DN has not been fully elucidated. Here, we studied the pharmacological effects of andrographolide against the progression of DN and high glucose-induced mesangial dysfunction. Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). After 1 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Diabetic mice were intraperitoneal injected with andrographolide (2 mg/kg, twice a week). After 8 weeks, functional and histological analyses were carried out. Parallel experiments uncovering the molecular mechanism by which andrographolide prevents from DN was performed in mesangial cells. Andrographolide inhibited the increases in fasting blood glucose, triglyceride, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. Andrographolide also prevented renal hypertrophy and ECM accumulation. Furthermore, andrographolide markedly attenuated NOX1 expression, ROS production and pro-inflammatory cytokines as well. Additionally, andrographolide inhibited Akt/NF-κB signaling pathway. These results demonstrate that andrographolide is protective against the progression of experimental DN by inhibiting renal oxidative stress, inflammation and fibrosis.

Ji X ，Li C ，Ou Y ，Li N ，Yuan K ，Yang G ，Chen X ，Yang Z ，Liu B ，Cheung WW ，Wang L ，Huang R ，Lan T ... -  《-》

Nepeta angustifolia C. Y. Wu improves renal injury in HFD/STZ-induced diabetic nephropathy and inhibits oxidative stress-induced apoptosis of mesangial cells.

As an important medicinal material constituting a variety of traditional Chinese medicine prescriptions, Nepeta angustifolia C. Y. Wu was used as a folk medicine to treat various vascular-related diseases including apoplexia, and cerebral haemorrhage in Tibet, China. Our previous studies have shown that this plant had a significant protective effect on vascular dysfunction of the intracerebral haemorrhage and diabetic rats. In present study, we aimed to investigate the protective effects and underlying mechanisms of Nepeta angustifolia on diabetic nephropathy (DN), a microvascular complication. This study is aim to evaluate the protective effect of ethanol extracts of N. angustifolia (NA) on DN, and explore mechanism of action to provide basis for its pharmacological action against DN. High-fat diet and low-dose streptozotocin administration (HFD/STZ) induced diabetic rats were randomly divided into 5 groups (n = 8): the diabetic model group, metformin group, and three dose groups of NA (60 mg/kg, 120 mg/kg, 240 mg/kg). After administration of NA for 8 weeks, the blood, urine and renal tissue were collected for subsequent experiments. Biochemical markers (urine protein, Cr, BUN), oxidative stress makers (SOD, GSH-px and MDA) and pro-inflammatory mediators (TNF-α, IL-1β, IL-6 and MCP-1) were evaluated by commercial kit and ELISA, respectively. The effect of NA on DN was further confirmed by evaluation of renal histopathology by using the H&E, PAS and Masson staining. The H2O2-induced HBZY-1 cells (rat glomerular mesangial cells) were also been used to evaluate the renal protective effect of NA (50 μg/mL, 100 μg/mL, 200 μg/mL). The oxidative stress makers were detected by commercial kit. The levels of apoptosis and related proteins (caspase 3, 9) were detected by TUNEL assay and western blot analysis, respectively. The depolarization of mitochondrial membrane potential was detected by JC-1 staining assay. The administration of NA is helpful to maintain near normal body weight, blood glucose, urine volume, urine protein, kidney index and serum levels of Cr and BUN. NA treatment significantly improve renal dysfunction by the down-regulation of renal oxidative stress and pro-inflammatory mediators in HFD/STZ induced diabetic rats. In vitro experiments, NA has a significant cellular protective effect in H2O2-induced HBZY-1 cells, as well as the regulation in increases of SOD level and the decreases of ROS and MDA levels. Furthermore, NA treatment can significantly inhibit H2O2 induced mesangial cells apoptosis by the increasing mitochondrial potential and suppressing caspases-madiated signaling pathway. NA has obvious improvement on renal dysfunction in HFD/STZ induced diabetic rats. NA can protect mesangial cells by inhibiting oxidative stress induced apoptosis, which may be related to its regulation of mitochondrial-caspase apoptosis pathway.

Huang S ，Tan M ，Guo F ，Dong L ，Liu Z ，Yuan R ，Dongzhi Z ，Lee DS ，Wang Y ，Li B ... -  《-》

Protective effect of ginsenoside metabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-κB/p38 signaling pathway in high-fat diet/streptozotocin-induced diabetic mice.

Though the antidiabetic effect of ginsenoside compound K (CK) has been well studied, the effect of CK on diabetic nephropathy (DN) is not clear. Whether CK would have a protective effect against DN and it could exert the protective effect by inhibiting the oxidative stress, NLRP3 inflammasome and NF-κB/p38 signaling pathway were investigated in this study. Here, the HFD (high fat diet)/STZ (streptozotocin)-induced DN mice model was established to assess the CK effect in vivo. Parallel experiments uncovering the molecular mechanism by which CK prevents from DN was performed in rat glomerular mesangial cell line HBZY-1 exposed to high glucose. CK (10, 20, 40 mg/kg/day) were intragastrically administered for 8 weeks, the general status, biochemical parameters, renal pathological changes and oxidative stress-parameters were observed, and the NLRP3 inflammasome and NF-κB/p38 signaling pathway were evaluated. The results showed that the elevated fasting blood glucose, serum creatinine, blood urea nitrogen and 24-hour urine protein of the DN mice were significantly decreased, and the proliferation of glomerular mesangial matrix was alleviated by CK. In addition, the generation of ROS in the kidney was significantly decreased, and the expression of Nox1 and Nox4 proteins were down-regulated. Further, the expression of NLRP3 inflammasome components (NLRP3, ASC and Caspase-1) and the inflammatory cytokines IL-1β and IL-18 were also significantly down-regulated in vivo and in vitro. The phosphorylation of renal p38 MAPK was also inhibited by CK. MCC950 (an inhibitor of NLRP3 inflammasome) and VX-765 (a Caspase-1 Inhibitor) showed significant interaction with CK on the decrease of IL-1β concentration in HBZY-1 cells. In conclusion, our study provided evidence that the protective effect of CK on diabetes-induced renal injury is associated with down-regulating the expression of NADHP oxidase, and inhibition of ROS-mediated activation of NLRP3 inflammasome and NF-κB/p38 signaling pathway, suggesting its therapeutic implication for renal inflammation.

Song W ，Wei L ，Du Y ，Wang Y ，Jiang S ... -  《-》

BAY 11-7082 ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated oxidative stress and renal inflammation via NF-κB pathway.

Diabetic nephropathy is a serious microvascular complication for patients associated with diabetes mellitus. Recent studies have suggested that NF-κB is the main transcription factor for the inflammatory response mediated progression of diabetic nephropathy. Hence, the present study is hypothesized to explore the renoprotective nature of BAY 11-7082 an IκB phosphorylation inhibitor on Streptozotocin (STZ) induced diabetic nephropathy in Sprague-Dawley (SD) rats. Male SD rats were divided into five groups, group I sham control, group II drug control, group III diabetic control (STZ 50mg/kg), group IV and V are test drug groups to which a single dose of STZ 50mg/kg was injected initially and later received BAY 11-7082 1mg/kg and 3mg/kg, respectively from 5th to 8th week. Eight weeks after STZ injection, diabetic rats exhibited significant renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, urea nitrogen and creatinine, which were reversed to near normal by BAY 11-7082. BAY 11-7082 treated rats showed significant improvement in the decreased enzymatic antioxidant SOD, non-enzymatic antioxidant GSH levels, and elevated lipid peroxidation and nitric oxide levels as observed in the diabetic rats. BAY 11-7082 treatment was found to significantly recover kidney histological architecture in the diabetic rats. Altered levels of inflammatory cytokines like TNF-α, IL-1β, IL-6 and nuclear transcriptional factor subunit NF-κB p65 were reverted to the normal level upon treatment with BAY 11-7082. Our results suggest that by limiting the activation of NF-κB, thereby reducing the expression of inflammatory cytokines and by inhibiting the oxidative damage BAY 11-7082 protect the rats against diabetic nephropathy.

Kolati SR ，Kasala ER ，Bodduluru LN ，Mahareddy JR ，Uppulapu SK ，Gogoi R ，Barua CC ，Lahkar M ... -  《-》

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 《-》