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1.
Article in Chinese | WPRIM | ID: wpr-940549

ABSTRACT

ObjectiveTo investigate the intervention effect of Danggui Buxuetang on oxidative stress and inflammatory response in diabetic kidney disease (DKD) rats from its improvement of podocyte mitochondrial dysfunction. MethodSD rats were randomly divided into the control group and modeling group, and the ones in the latter group rats were fed a high-glucose and high-fat diet and then intraperitoneally injected with a small dose of streptozotocin (STZ) for inducing type 2 diabetes. The successfully modeled rats were randomized into the model group, high- and low-dose (1.44 and 0.72 g·kg-1) Danggui Buxuetang groups, and irbesartan (0.017 g·kg-1)group and gavaged with the corresponding drugs, while those in the normal and model groups with an equal volume of normal saline. After 20 weeks of drug intervention, the urinary microalbumin-to-urine creatinine ratio (UACR) and serum malondialdehyde (MDA) content and manganese superoxide dismutase (MnSOD) activity in each group were measured. The pathological changes in renal tissue were observed by Masson trichrome staining, and periodic acid-silver metheramine (PASM) staining, followed by the observation of ultrastructural changes in podocytes under the transmission electron microscope (TEM). The expression level of reactive oxygen species (ROS) in rat kidney tissue was detected using a fluorescent probe dihydroethidium (DHE). The protein expression levels of peroxisome proliferator-activated receptor γ -coactivator -1α (PGC-1α), nucleotide-binding domain like receptor protein 3 (NLRP3), and Wilms tumor protein-1 (WT-1) were measured by immunohistochemistry (IHC), and the expression levels of NLRP3, interleukin-1β (IL-1β),and WT-1 in podocytes by immunofluorescence (IF) assay. The mRNA expression levels of PGC-1α and NLRP3 in the renal tissues were determined by real-time fluorescence quantitative polymerase chain reaction (Real-time PCR), and the protein expression levels of PGC-1α, MnSOD, NLRP3, and IL-1β were assayed by Western blot. ResultCompared with the normal group, the model group exhibited elevated UACR and MDA content, weakened MnSOD activity (P<0.01), glomerular hypertrophy, thickened basement membrane, mesangial hyperplasia, increased extracellular matrix, K-W nodules, podocyte mitochondrial swelling, disordered mitochondrial cristae, foot process fusion or loss, vacuolization, increased ROS (P<0.01), enhanced NLRP3 and IL-1β but diminished WT-1 expression in podocytes, down-regulated PGC-1α mRNA expression (P<0.01) and PGC-1α and MnSOD protein expression (P<0.01), and up-regulated NLRP3 mRNA expression and NLRP3 and IL-1β protein expression (P<0.01). Compared with the model group, Danggui Buxuetang high-dose group significantly decreased UACR and MDA, enhanced MnSOD activity (P<0.05, P<0.01), improved renal histopathology and podocyte mitochondrial ultrastructure, decreased ROS (P<0.05, P<0.01) and NLRP3 and IL-1β expression in podocytes, enhanced WT-1 expression in podocytes, up-regulated the mRNA and protein levels of PGC-1α and MnSOD, and down-regulated the mRNA and protein levels of NLRP3 and IL-1β (P<0.05, P<0.01). ConclusionDanggui Buxuetang alleviates oxidative stress, reduces inflammatory response, protects kidney, and delays the progression of DKD possibly by improving the mitochondrial dysfunction in podocytes of DKD rats.

2.
Article in Chinese | WPRIM | ID: wpr-940550

ABSTRACT

ObjectiveTo observe the effect of Danggui Buxuetang on the podocyte injury and receptor-interacting protein kinase 1/receptor-interacting protein kinase3/mixed lineage kinase domain-like protein (RIPK1/RIPK3/MLKL) signaling pathway in diabetic kidney disease (DKD) ratsand to explore its possible mechanism against DKD. MethodEight of the 50 SD rats were randomly classified intoa normal group, and the remaining were fed a high-glucose and high-fat diet for six weeks and then intraperitoneally injected with 0.035 g·kg-1streptozotocin (STZ) for inducing type 2 diabetes. After successful modeling,they were randomized into the model group,high- and low-dose (1.44,0.72 g·kg-1) Danggui Buxuetang groups, and irbesartan (0.017 g·kg-1)group. After 20 weeks of drug intervention, the fasting blood glucose (FBG), kidney index (KI),and urinary microalbumin-to-urine creatinine ratio (UACR)were detected in each group. The pathological changes in renal tissue were observed by hematoxylin-eosin (HE) staining, followed by the observation of ultrastructural changes in podocytes under the transmission electron microscope. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in renal tissue of rats were determined by enzyme-linked immunosorbent assay (ELISA), and the protein expression levels of RIPK1, RIPK3, and MLKL in rat kidney tissue by immunohistochemistry. The apoptosis rate of podocytes was detected by in situ nick end-labeling (TUNEL) assay. The mRNA expression levels of RIPK1, RIPK3, and MLKL in kidney tissue of rats were measured by real-time fluorescence quantitative polymerase chain reaction (Real-time PCR), and the protein expression levels of RIPK, RIPK3, and MLKL and podocyte marker Wilms tumor protein-1 (WT-1) in rat kidney tissue were assayed by Western blot. ResultCompared with the normal group, the model group exhibited elevated FBG, UACR, and KI (P<0.01), glomerular hypertrophy, thickened basement membrane, increased extracellular matrix, mesangial hyperplasia, foot process fusion or loss, enhanced apoptosis in renal tissue, up-regulated TNF-α and IL-6 levels (P<0.01) and RIPK1/RIPK3/MLKL mRNA and protein expression (P<0.01), and down-regulated WT-1 protein expression. Compared with the model group, Danggui Buxuetang high-dose group significantly reduced the levels of FBG, UACR, and KI, improved renal histopathology, podocyte loss, and apoptosis in renal tissue, down-regulated TNF-α and IL-6 levels and RIPK1/RIPK3/MLKL mRNA and protein expression (P<0.05, P<0.01), and up-regulated WT-1 protein expression. ConclusionDanggui Buxuetang alleviates podocyte injury and delays the development of DKD possibly by regulating the RIPK1/RIPK3/MLKL signaling pathway.

3.
Article in Chinese | WPRIM | ID: wpr-940551

ABSTRACT

ObjectiveTo observe the effect of Danggui Buxuetang on podocyte pyroptosis in diabetic kidney disease (DKD) rats and to explore the possible mechanism of its prevention and treatment of DKD and podocyte pyroptosis. MethodEight of the 50 male SD rats were randomly classified into a normal group, and the remaining 42 were fed a high-glucose and high-fat diet for six weeks and then intraperitoneally injected with 35 mg·kg-1 streptozotocin (STZ) for inducing type 2 diabetes. After successful modeling, they were randomized into the model group, low- (0.72 g·kg-1) and high-dose (1.44 g·kg-1) Danggui Buxuetang group, and irbesartan (0.017 g·kg-1) group and gavaged with the corresponding drugs, while those in the normal group and model group with an equal volume of normal saline, once per day, for 20 weeks. During the medication, the fasting blood glucose (FBG) and 24 h urine protein (24 h-UTP) were measured regularly. After administration, the pathological changes in renal tissues were observed by periodic acid-silver metheramine (PASM) staining, followed by the observation of ultrastructural changes in podocytes under the transmission electron microscope (TEM). Serum levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) were determined by enzyme-linked immunosorbent assay (ELISA). The DNA damage in renal tissue cells of rats was detected by in situ nick end-labeling (TUNEL) assay. The protein expression levels of thioredoxin interacting protein (TXNIP), cysteine-dependent aspartate-directed protease-1 (Caspase-1), and gasdermin D (GSDMD) in renal tissues of rats were detected by immunohistochemistry (IHC), the expression levels of nucleotide binding domain like receptor protein 3 (NLRP3) and Wilms tumor protein-1 (WT-1) in podocytes by immunofluorescent (IF) staining, and the expression levels of TXNIP/NLRP3/Caspase-1/GSDMD pathway proteins and Synaptopodin in renal podocytes by Western blot. ResultCompared with the normal group, the model group exhibited increased FBG and 24 h UTP, glomerular hypertrophy, mesangial hyperplasia, increased extracellular matrix, thickened basement membrane, K-W nodules, vacuolar degeneration in renal tubular epithelial cells, foot process fusion or loss, elevated serum IL-1β and IL-18 levels and TUNEL-positive cells in renal tissue, enhanced NLRP3 but diminished WT-1 expression in podocytes, down-regulated Synaptopodin protein expression, and up-regulated TXNIP/NLRP3/Caspase-1/GSDMD protein expression (P<0.01). Compared with the model group, Danggui Buxuetang high-dose group remarkably lowered FBG, 24-h UTP, and TUNEL-positive cells in renal tissue, improved renal histopathology and podocyte injury and loss, down-regulated NLRP3 expression in podocytes and TXNIP/NLRP3/Caspase-1/GSDMD protein expression levels, and up-regulated WT-1 expression in podocytes and Synaptopodin protein expression (P<0.05, P<0.01). ConclusionDanggui Buxuetang inhibits podocyte pyroptosis to reduce proteinuria and delays the development of DKD possibly by regulating the TXNIP/NLRP3/GSDMD signaling pathway.

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