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Hirsutella sinensis Treatment Shows Protective Effects on Renal Injury and Metabolic Modulation in db/db Mice.

ABSTRACT: Hirsutella sinensis (HS) is the anamorph of the traditional Chinese medicine Cordyceps sinensis. Although the renal protective effect of HS has been reported, its effect on diabetic nephropathy (DN) remains unclear. In this study, db/db mice were used as the DN model, and the renal protective effect was evaluated after oral administration of HS for 6 and 12 weeks. Plasma, urine, and kidney samples were collected, and biochemical indicator measurements, pathological analysis, and metabolomics studies were performed. Biochemical assays showed that HS reduced the levels of fasting blood glucose (FBG), urinary albumin/creatinine ratio (ACR), and N-acetyl-beta-D-glucosaminidase (NAG) and increased the creatinine clearance (Ccr). HS alleviated glomerular and tubular glycogen accumulation and fibrosis and normalized the disordered ultrastructure of the glomerular filtration barrier. Metabolomics analysis of metabolites in the plasma, urine, and kidney indicated that HS modulated the perturbed glycolipid metabolism and amino acid turnover. HS reduced the elevated levels of metabolites involved in energy metabolism (TCA cycle, glycolysis, and pentose phosphate pathway) and nucleotide metabolism (pyrimidine metabolism and purine metabolism) in the kidneys of db/db mice. These results suggest that HS can protect against renal injury and that its efficacy involved metabolic modulation of the disturbed metabolome in db/db mice.

SUBMITTER: Lu Z

PROVIDER: S-EPMC6475559 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Hirsutella sinensis Treatment Shows Protective Effects on Renal Injury and Metabolic Modulation in db/db Mice.

Lu Zhenyao Z Li Sijia S Sun Runbin R Jia Xue X Xu Chen C Aa Jiye J Wang Guangji G Wang Guangji G

Evidence-based complementary and alternative medicine : eCAM 20190404

Hirsutella sinensis (HS) is the anamorph of the traditional Chinese medicine Cordyceps sinensis. Although the renal protective effect of HS has been reported, its effect on diabetic nephropathy (DN) remains unclear. In this study, db/db mice were used as the DN model, and the renal protective effect was evaluated after oral administration of HS for 6 and 12 weeks. Plasma, urine, and kidney samples were collected, and biochemical indicator measurements, pathological analysis, and me ...[more]

PMID: 31080482

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Project description:This study investigated the hypoglycemic and renal protective effects of scutellarin (SCU) in db/db mice and elucidated the underlying mechanisms. The oral administration of metformin hydrochloride (Met) at 120?mg/kg and SCU at 25, 50, and 100?mg/kg over an eight-week period had hypoglycemic effects, demonstrated by decreases in body weight, blood glucose, food and water intake, and glycated hemoglobin activity and by augmented insulin levels and pyruvate kinase activity in the serum of db/db mice. SCU alleviated dyslipidemia by decreasing the levels of triglycerides and total cholesterol and enhancing the levels of high-density lipoprotein cholesterol in the serum of db/db mice. SCU reversed the overexpression of mRNA of renal damage markers (receptor for advanced glycation end products, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1), macrophage marker CD11b, and T cell marker CD3 in kidney of db/db mice. Pathological examination confirmed that SCU improved the organ structures of hyperglycemia-damaged livers, kidneys, and pancreas islets. Antibody array assay and enzyme-linked immunosorbent assay were combined to screen and analyze the regulatory effects of SCU on inflammatory factors and oxidative enzymes. SCU exerted anti-inflammatory effects by inhibiting the levels of proinflammatory cytokines (glycogen synthase kinase, intercellular adhesion molecule 2, and interleukin 1? and 2) and promoting anti-inflammatory cytokines (interleukin 4). SCU decreased the reactive oxygen species and malondialdehyde concentrations and increased the activity levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) in serum and kidneys. Furthermore, SCU upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which in turn improved heme oxygenase 1 (HO-1), superoxide dismutase 1 and 2, and catalase expression levels in kidneys. The study showed that SCU has at least partial hypoglycemic and renal protective effects in db/db mice, and the mechanism is the modulation of the Nrf2/HO-1 signaling pathway.

Project description:QiDiTangShen granules (QDTS) have been proven to reduce the proteinuria in patients with diabetic nephropathy (DN) effectively. The present study was aimed to investigate the mechanism underlying QDTS's renoprotection. The main components of QDTS were identified by ultra-high liquid chromatography-tandem mass spectrometry and pharmacological databases, among which active components were screened by oral bioavailability and drug-likeness. Their regulation on autophagy-related nutrient-sensing signal molecules (AMPK, SIRT1, and mTOR) was retrieved and analyzed through the Pubmed database. Then, db/db mice were randomly divided into three groups (model control, valsartan and QDTS), and given intragastric administration for 12 weeks, separately. Fasting and random blood glucose, body weight, urinary albumin excretion (UAE) and injury markers of liver and kidney were investigated to evaluate the effects and safety. Renal histological lesions were assessed, and the expressions of proteins related to nutrient-sensing signals and autophagy were investigated. Thirteen active components were screened from 78 components identified. Over half the components had already been reported to improve nutrient-sensing signals. QDTS significantly reduced UAE, ameliorated mesangial matrix deposition, alleviate the expression of protein and mRNA of TGF-β, α-SMA, and Col I, as well as improved the quality of mitochondria and the number of autophagic vesicles of renal tubular cells although the blood glucose was not decreased in db/db mice. Compared to the db/db group, the expression of the autophagy-inducible protein (Atg14 and Beclin1) and microtubule-associated protein 1 light chain 3-II (LC3-II) were up-regulated, autophagic substrate transporter p62 was down-regulated in QDTS group. It was also found that the expression of SIRT1 and the proportion of p-AMPK (thr172)/AMPK were increased, while the p-mTOR (ser2448)/mTOR ratio was decreased after QDTS treatment in db/db mice, which was consistent with the effect of its active ingredients on the nutrient-sensing signal pathway as reported previously. Therefore, QDTS may prevent the progression of DN by offering the anti-fibrotic effect. The renoprotection is probably attributable to the regulation of nutrient-sensing signal pathways, which activates autophagy.

Project description:ObjectiveTo investigate the inhibitory effect of Hirsutella sinensis (HS) on epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells induced by aristolochic acid (AA) and its possible mechanism.Methods18 male Sprague-Dawley rats were randomly and equally divided into the following 3 groups: AA group, AA+HS group and control group. Urinary protein excretion and creatinine clearance (CCr) were measured. All rats were sacrificed at the end of 12th week. The pathological examination of renal tissue was performed and the mRNA and protein expression of transforming growth factor-?1 (TGF-?1), ?-smooth muscle actin (?-SMA), cytokeratin-18 and Snail in renal cortex were determined by real time quantitative PCR and immunohistochemical staining respectively. In addition, human renal proximal tubule epithelial cells line (HKC) was divided into the following 4 groups: AA group, AA+HS group, HS control group and control group. The above mRNA and protein expression in HKC was determined by real time quantitative PCR and Western blot respectively.Results(1) CCr was significantly decreased, and the urinary protein excretion and relative area of renal interstitial fibrosis were significantly increased in the rats of AA and AA+HS group compared to those in control group (P<0.05 or P<0.01); all the above abnormalities significantly lightened in the rats of AA+HS group compared to those in AA group (P<0.05). (2) The mRNA and protein expression of TGF-?1, ?-SMA and Snail was significantly up-regulated and the expression of cytokeratin-18 was significantly down-regulated in the rat renal cortex as well as in the cultured HKC cells in AA and AA+HS groups compared to those in control group (P<0.05 or P<0.01); all the above abnormalities significantly alleviated in AA+HS group compared to those in AA group (P<0.05 or P<0.01). (3) Knockdown endogenous Snail expression by siRNA could ameliorate AA-induced EMT of HKC cells, while overexpression of Snail by plasmid transfection diminished the antagonistic effect of HS on AA-induced EMT. These results suggest Snail might be a potential target of HS effect.ConclusionHS is able to antagonize, to some extent, tubular EMT and renal interstitial fibrosis caused by AA, which might be related to its inhibitory effects on the TGF-?1 and Snail expression.

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Hirsutella sinensis Treatment Shows Protective Effects on Renal Injury and Metabolic Modulation in db/db Mice.

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<i>Hirsutella sinensis</i> Treatment Shows Protective Effects on Renal Injury and Metabolic Modulation in db/db Mice.

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