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Shen Qi Wan attenuates renal interstitial fibrosis through upregulating AQP1

Chinese Journal of Natural Medicines 2023年第5期21卷 359-370页

作者： LIN Yiyou WEI Jiale ZHANG Yehui HUANG Junhao WANG Sichen LUO Qihan YU Hongxia JI Liting ZHOU Xiaojie LI Changyu School of Pharmaceutical Sciences Zhejiang Chinese Medical UniversityHangzhou 310053China Academy of Chinese Medical Sciences Zhejiang Chinese Medical UniversityHangzhou 310053China

renal interstitial fibrosis(RIF)is the crucial pathway in chronic kidney disease(CKD)leading to the end-stage renal failure.However,the underlying mechanism of Shen Qi Wan(SQW)on RIF is not fully understood.In the current study,we investigated the role of Aquaporin 1(AQP1)in SQW on tubular epithelial-to-mesenchymal transition(EMT).A RIF mouse model induced by adenine and a TGF-β1-stimulated HK-2 cell model were etablished to explore the involvement of AQP 1 in the protective effect of SQW on EMT in vitro and in vivo.Subsequently,the molecular mechanism of SQW on EMT was explored in HK-2 cells with AQP1 knockdown.The results indicated that SQW alleviated kidney injury and renal collagen deposition in the kidneys of mice induced by adenine,increased the protein expression of E-cadherin and AQP1 expression,and decreased the expression of vimentin andα-smooth muscle actin(α-SMA).Similarly,treatmement with SQW-containing serum significantly halted EMT process in TGF-β1 stimulated HK-2 cells.The expression of snail and slug was significantly upregulated in HK-2 cells after knockdown of AQP1.AQP1 knockdown also increased the mRNA expression of vimentin andα-SMA,and decreased the expression of E-cadherin.The protein expression of vimentin increased,while the expression of E-cadherin and CK-18 significantly decreased after AQP1 knockdown in HK-2 cells.These results revealed that AQP1 knockdown promoted EMT.Furthermore,AQP1 knockdown abolished the protective effect of SQW-containing serum on EMT in HK-2 cells.In sum,SQW attentuates EMT process in RIF through upregulation of the expression of AQP1.

关键词： Shen Qi Wan Chronic kidney disease renal interstitial fibrosis Epithelial to mesenchymal transition Aquaporin 1

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Chinese herbal decoction astragalus and angelica exerts its therapeutic effect on renal interstitial fibrosis through the inhibition of MAPK,PI3K-Akt and TNF signaling pathways

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Genes & Diseases 2022年第2期9卷 510-521页

作者： Hao Yuan Xuelian Wu Xiaomin Wang Chengfu Yuan College of Medical Science China Three Gorges UniversityYichangHubei 443002PR China BGI Education Center University of Chinese Academy of SciencesShenzhenGuangdong 518083PR China Chumeiren Medical Cosmetic Clinic WuJiaGang DistrictYichangHubei 443002PR China

Astragalus and Angelica decoction(A&A)has been clinically used as a classical traditional Chinese medicine(TCM)formula in China for many years for the treatment of kidney diseases,especially renal interstitial fibrosis(RIF).However,the mechanisms underlying the therapeutic effects of A&A on RIF remains poorly understood.In the present study,systematic network pharmacology and effective experimental verification were utilized for the first time to elucidate the pharmacological efficacy and potential mechanism.The outcomes indicated that 22 active components and 87 target genes of A&A were identified and cross-referenced with RIF-associated genes,contributing to confirmation of 74 target genes of A&A for RIF.Pathway and functional enrichment analyses revealed that A&A had substantial effects on MAPK,PI3K-Akt and TNF signaling pathways.In addition,seven core targets with relatively higher betweenness and degree were identified in the constructed Chinese medicine material-chemical component-target-signal pathway network.Moreover,we verified the potential therapeutic effect of A&A in vivo(using a mouse model of RIF),confirming that A&A could effectively protect the kidney by regulating these target genes.The therapeutic effect of A&A on RIF could be attributed to its role in regulating the cell cycle,limiting the apoptosis,and inhibiting the inflammation.

关键词： Active components Astragalus and angelica decoction Network pharmacology renal interstitial fibrosis Target gene

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Fuzheng Huayu recipe, a traditional Chinese compound herbal medicine, attenuates renal interstitial fibrosis via targeting the miR-21/PTEN/AKT axis

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Journal of Integrative Medicine 2020年第6期18卷 505-513页

作者： Qing-lan Wang Yan-yan Tao Hong-dong Xie Cheng-hai Liu Ping Liu Teaching&Research Department of Clinical and Classic Medicine College of Basic Medical Science.Shanghai University of Traditional Chinese MedicineShanghai 201203.China E-institute of Shanghai Municipal Education Committee Shanghai University of Traditional Chinese MedicineShanghai 210203China Institute of Liver Diseases Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai 210203China

Objective: MicroRNAs(miRNAs) may be viable targets for treating renal interstitial fibrosis(RIF). Fuzheng Huayu recipe(FZHY), a traditional Chinese compound herbal medicine, is often used in China to treat fibrosis. This study sought to assess the mechanisms through which FZHY influences miRNAs to treat RIF.Methods: RIF was induced in rats by mercury chloride and treated with FZHY. Hydroxyproline content,Masson’s staining and type I collagen expression were used to evaluate renal collagen deposition.renal miRNA profiles were evaluated using a miRNA microarray. Those miRNAs that were differentially expressed following FZHY treatment were identified and subjected to bioinformatic analyses. The miR-21 target gene phosphatase and tensin homolog(PTEN) expression and AKT phosphorylation in kidney tissues were assessed via Western blotting. In addition, HK-2 human proximal tubule epithelial cells were treated using angiotensin II(Ang-II) to induce epithelial-to-mesenchymal transition(EMT), followed by FZHY exposure. miR-21 and PTEN expressions were evaluated via quantitative reverse transcriptionpolymerase chain reaction(qRT-PCR), while E-cadherin and a-smooth muscle actin(a-SMA) expressions were assessed by immunofluorescent staining and qRT-PCR. Western blotting was used to assess PTEN and AKT phosphorylation.Results: FZHY significantly decreased kidney collagen deposition, hydroxyproline content and type I collagen level. The miRNA microarray identified 20 miRNAs that were differentially expressed in response to FZHY treatment. Subsequent bioinformatic analyses found that miR-21 was the key fibrosis-related miRNA regulated by FZHY. FZHY also decreased PTEN expression and AKT phosphorylation in fibrotic kidneys. Results from in vitro tests also suggested that FZHY promoted E-cadherin upregulation and inhibited a-SMA expression in Ang-II-treated HK-2 cells, effectively reversing Ang-II-mediated EMT. We also determined that FZHY reduced miR-21 expression, increased PTEN expression and decreased AKT phosphorylation in th

关键词： Fuzheng Huayu recipe Chinese herbal medicine renal interstitial fibrosis miR-21 PTEN AKT microRNA

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Huangqi decoction(黄芪汤) attenuates renal interstitial fibrosis via transforming growth factor-β1/mitogen-activated protein kinase signaling pathways in 5/6 nephrectomy mice

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Journal of Traditional Chinese Medicine 2022年第5期42卷 723-731页

作者： ZHAO Jie WANG Li CAO Ai-li WANG Yun-man CHI Yang-feng WANG Yi WANG Hao PENG Wen Department of Chinese Medicine/Department of Chinese Integrative Medicine The First Affiliated HospitalAnhui Medical UniversityHefei 230022China Department of Nephrology Putuo Hospital affiliated to Shanghai University of Chinese MedicineShanghai 200062China Laboratory of renal Disease Putuo HospitalShanghai University of Chinese MedicineShanghai 200062China

OBJECTIVE: To investigate the effect of Huangqi decoction( 黄芪汤) on renal interstitial fibrosis and its association with the transforming growth factor-β1(TGF-β1)/mitogen-activated protein kinase(MAPK) signaling pathway. METHODS: 120 C57/BL mice were randomly divided into six groups: sham group, Enalapril(20 mg/kg) group, 5/6 nephrectomy model group, and 5/6 nephrectomy model plus Huangqicoction(0.12, 0.36 and 1.08 g/kg respectively) groups. Detecting 24hours urinary protein, blood pressure, serum creatinine, urea nitrogen content changes. Periodic Acid-Schiff stain(PAS) and Masson’s trichrome staining was used to observe the renal tissue pathological changes. Protein expression of TGF-β1, Phosphorylated P38 mitogen activated protein kinases(P-P38), Phosphorylated c-jun N-terminal kinase(P-JNK), Phosphorylated extracellular regulated proteinhnase(PERK), Fibroblast-specific protein-1(FSP-1), Alpha smooth muscle actin(α-SMA), Type Ⅲ collagen(Collagen Ⅲ), Connective tissue growth factor(CTGF),Bcl-2 Assaciated X protein(Bax) and B cell lymphoma 2(Bcl-2) were measured with western blot and immunohistochemical. RESULTS: Both Huangqi decoction and Enalapril improved the kidney function, 24 h urinary protein and the fibrosis in 5/6 nephrectomy mice, Huangqi decoction downregulated the expressions of TGF-β1, FSP-1, α-SMA, Collagen Ⅲ and CTGF in a dose-dependent manner, and it has a significant difference(P renal interstitial fibrosis in 5/6 nephrectomized mice via the inhibition of EpithelialMesenchymal Transitions and downregulating the TGF-β1/MAPK signaling pathway.

关键词： nephrectomy transforming growth factor beta1 mitogen-activated protein kinases Signal transduction renal interstitial fibrosis Huangqi decoction

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Interventional mechanisms of herbs or herbal extracts on renal interstitial fibrosis

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Journal of Integrative Medicine 2016年第3期14卷 165-173页

作者： Jia Xia Li-qun He Xiao Su Department of Nephrology Shuguang Hospital Shanghai University of Traditional Chinese Medicine Department of Rheumatology Shanghai Municipal Hospital of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine

renal interstitial fibrosis（RIF） is a common development in chronic renal diseases that can lead to uremia and be life-threatening. The RIF pathology has complicated extracellular and intercellular mechanisms, involving many cells and cytokines, resulting in an incomplete mechanistic understanding of the disease. Finding effective herbs or herbal extracts for prevention and treatment of RIF is crucial because current medical approaches do not reliably slow or reverse RIF. In recent years, many experts have worked to identify herbs or herbal extracts to combat RIF both in vivo and in vitro, with some success. This review attempts to summarize the possible interventional mechanisms of herbs or herbal extracts involved in protecting and reversing RIF. The authors found some herbs and their extracts that may ameliorate renal impairments through anti-inflammation, anti-fibrogenesis and stabilization of extra cellular matrix. Among them, tetramethylpyrazine/ligustrazine, curcumin and polyglucoside of Tripterygium have experimentally shown good potential for improving RIF. However, conclusive evidence is still needed, especially in randomized controlled clinical trials. We expect that herbs or herbal extracts will play an important role in RIF treatment and reversal in the future.

关键词： renal interstitial fibrosis plant extracts drugs,Chinese herbal review

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Mechanisms of renal interstitial fibrosis: cross-talk between mitophagy and NLRP3 inflammasome

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Microenvironment & Microecology Research 2023年第3期5卷 24-29页

作者： Wen-Ze Jiang Ke-Da Lu Zhen-Liang Fan The First Clinical Medical College of Zhejiang Chinese Medical University Hangzhou 310053China Department of Nephrology The Third Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou 310005China Department of Nephrology The First Affiliated Hospital of Zhejiang Chinese Medical University(Zhejiang Provincial Hospital of Chinese Medicine)Hangzhou 310003China.

renal interstitial fibrosis(RIF)is the main pathological basis leading to end-stage renal disease,and is closely related to the prognosis of patients with kidney disease.Increasing evidence as shown that mitophagy and NLRP3 inflammasome play important roles in the pathogenesis of RIF.Studies suggest that inhibiting NLRP3 inflammasome by activating mitophagy can prevent and alleviate RIF.This review summarizes role played by cross-talk between mitophagy and NLRP3 inflammasome in promoting RIF,so as to offer new perspectives on more effective slow the progression of renal diseases and fibrosis prevention.

关键词： renal interstitial fibrosis mitophagy NLRP3 inflammasome

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Correlation between the Expression of TGF-β1,Rhoa,SOX9 and renal interstitial fibrosis in Rats with Chronic Kidney Disease

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中国生物医学工程学报:英文版 2023年第2期32卷 65-72页

作者： GUO Chun-hua LI Hua-qing LIN Zheng QIU Zhao-wen DENG Jin-xiu ZHANG Qiu-xia LIN Yong Longyan First Affiliated Hospital of Fujian Medical University Fujian Longyan 364000China

Objective:To study the correlation between the expression of transforming growth factor-β1(TGF-β1),Rho A,SOX9 and renal interstitial fibrosis in rats with chronic kidney disease.Methods:Forty specific pathogen-free(SPF)male SD rats were randomly divided into study group and control group,with 20 cases in each group.The study group was given adenine suspension by gavage,while the control group was given the same amount of saline by gavage.Blood,urine and renal tissue specimens were collected from all rats at 3rd and 6th weeks after modeling.The kidney weight,kidney weight/body weight,renal function indexes,the expression of TGF-β1,Rho A and SOX9 m RNA in renal tissues,Masson staining and renal interstitial fibrosis score were compared between the two groups.Pearson correlation was used to analyze the relationship between the renal interstitial fibrosis score and the expression of TGF-β1,Rho A and SOX9 m RNA in renal tissues of rats with chronic kidney disease.Results:The kidney weight and kidney weight/body weight of rats in the study group were higher than those in the control group at 3rd and 6th weeks after modeling(Prenal tissues of rats in the study group were higher than those in the control group at 3rd and 6th weeks after modeling(Prenal interstitial fibrosis score in the study group was higher than that in the control group at 3rd and 6th weeks after modeling(Prenal interstitial fibrosis score in rats with chronic kidney disease was positively correlated with the expression of TGF-β1,Rho A and SOX9 m RNA in renal tissues(Prenal interstitial fibrosis,which m

关键词： chronic kidney disease transforming growth factor-β1(TGF-β1) RhoA SOX9 renal interstitial fibrosis correlation

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Fuzheng Huayu Formula(扶正化瘀方) Prevents Rat renal interstitial fibrosis Induced by HgCl2 via Antioxidative Stress and Down-regulation of Nuclear Factor-Kappa B Activity

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Chinese Journal of Integrative Medicine 2017年第8期23卷 598-604页

作者： YUAN Ji-li TAO Yan-yan WANG Qing-lan SHEN Li LIU Cheng-hai Institute of Liver Diseases Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shangha 201203 China Shanghai Key Laboratory of Traditiona Chinese Clinical Medicine Shanghai 201203 China E-Institute of TCM Internal Medicine Shanghai Municipa Education Commission Shanghai 201203 China

Objective：To investigate the mechanism of action of Fuzheng Huayu Formula（扶正化瘀方,FZHY）against renal interstitial fibrosis（RIF）relating to oxidative injury and nuclear factor-kappa B（NF-κB）activity.Methods：Thirty-two Sprague-Dawley rats were randomly divided into 3 groups：normal group,model group and FZHY treatment group.The RIF model was induced by oral administration of HgC l2 at a dose of 8 mg/kg body weight once a day for 9 weeks.Meanwhile,rats in FZHY treatment group orally took FZHY at a dose of4.0 g/kg rat weight for 9 weeks.The content of hydroxyproline（Hyp）and collagen deposition in kidney were observed.The activities of superoxide dismutase（SOD）and glutathione peroxidase（GSH-Px）,the content of glutathione（GSH）and malondialdehyde（MDA）of kidney were tested.The expressions of inhibitor-κappa B（IκB）,phospho-IκB（p-IκB）,tumor necrosis factor-α（TNF-α）,matrix metalloproteinase-2（MMP-2）andα-smooth muscle actin（α-SMA）were analyzed by Western blot.α-SMA expression was also observed by immunofluorescent staining.MMP-2 activity was measured by gelatin zymography.NF-κB activation was determined by electrophoretic mobility shift assay.Results：renal interstitial fibrosis was induced by Hg Cl2,demonstrated by remarkably increased Hyp contents and excessive collagen deposition in kidney（P〈0.01）.FZHY significantly inhibited renal interstitial collagen deposition and reduced Hyp content of the Hg Cl2-treated rats（P〈0.01）.GSH content decreased obviously,and MDA content increased significantly in HgC l2-treated rats compared with that of normal rats（P〈0.01）.FZHY significantly increased GSH content and decreased MDA content in the model rats（P〈0.01）.The expressionα-SMA was increased in model rats compared with that of normal rats,FZHY significantly decreased its expression（P〈0.01）.The expressions of p-IκB and TNF-αand MMP-2,MMP-2 activity,and NF-κB activation were increased in model group compared with that in normal group（P〈0.01）,FZHY significantly decreased NF-κB activation,MMP-2 activity and p-IκB and TNF-αexpressions（P〈0.01

关键词： Fuzheng Huayu Formula renal interstitial fibrosis mercuric chloride oxidative stress nuclearfactor-kappa B matrix metalloproteinase-2 tumor necrosis factor- α Chinese medicine

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Exploring the mechanism of Qinghaobiejiatang in treating renal interstitial fibrosis based on network pharmacology

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Medical Data Mining 2021年第2期4卷 35-48页

作者： Xing Wang Tian-Tian Deng Xia Li Beijing University of Chinese Medicine Beijing 100029China Dongzhimen Hospital Beijing University of Chinese Medicine Beijing 100700China

To explore the potential mechanism of the classic ancient prescription Qinghaobiejiatang(QHBJT)in treating renal interstitial fibrosis.Methods:Obtain the active ingredients of Qinghao(Artemisiae annuae herba),Biejia(Trionycis carapax),Dihuang(Rehmanniae radix),Zhimu(Anemarrhenae rhizoma),and Mudanpi(Moutan cortex)through TCMSP and TCMID databases.Collect disease targets through the GENECARDS database.Use Venny2.1.0 platform to draw Venn diagrams to map drugs and disease targets.Import the key targets into Cytoscape 3.7.2 software to draw a network diagram of“drugs-active ingredients-diseases-key targets”.The STRING11.0 database was used to construct the key target protein interaction network diagram.Use R language for Gene ontology function and kyoto encyclopedia of genes and genomes pathway enrichment analysis.Results:A total of 317 active ingredients were obtained through screening,involving 166 targets,and 102 active ingredients related to disease targets,mainly involved in the regulation of key targets such as FOS,IL6,MTOR,MAPK8,RELA,CCND1,TP53,EGFR,and CASP3 signal pathways related to viral infection,tumor-related,apoptosis,signal transduction,fluid shear stress and atherosclerosis play a synergistic role in the treatment of renal fibrosis.Conclusion:The effect mechanism of QHBJT in treating renal interstitial fibrosis is related to inflammation,oxidative stress,hypoxia,apoptosis,pathological activation and damage of renal tubular epithelial cells mediated by the above pathways.

关键词： Internet pharmacology Qing-Hao-Bie-Jia-Tang renal interstitial fibrosis Mechanism research Latent pathogen

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Involvement of hydrogen sulfide in the progression of renal fibrosis

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Chinese Medical Journal 2019年第23期132卷 2872-2880页

作者： Yu Wang Qi-Qi Xing Jing-Ke Tu Wen-Bin Tang Xiang-Ning Yuan Yan-Yun Xie Wei Wang Zhang-Zhe Peng Ling Huang Hui Xu Jiao Qin Xiang-Cheng Xiao Li-Jian Tao Qiong-Jing Yuan Reproductive Medicine Center Xiangya HospitalCentral South UniversityChangshaHunan 410008China Division of Orthopedics Department of SurgeryXiangya HospitalCentral South UniversityChangshaHunan 410008China Regenerative Medicine Clinic Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300041China Division of Nephrology Department of Internal MedicineXiangya HospitalCentral South UniversityChangshaHunan 410008China Division of Nephrology Department of Internal MedicineChangsha Central HospitalChangshaHunan 410008China

Objective:renal fibrosis is the most common manifestation of chronic kidney disease(CKD).Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it,there is an urgent need to identify novel therapies.Hydrogen sulfide(H2S)is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body.This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application.Data sources:Literature was collected from PubMed until February 2019,using the search terms including"Hydrogen sulfide,""Chronic kidney disease"Mrenal interstitial fibrosis,"Kidney disease,""Inflammation factor,""Oxidative stress,""Epithelialto-mesenchymal transition,""H2S donor,""Hypertensive kidney dysfunction,""Myofibroblasts,""Vascular remodeling,""transforming growth factor(TGF)-beta/Smads signaling,"and"Sulfate potassium channels."Study selection:Literature was mainly derived from English articles or articles that could be obtained with English abstracts.Article type was not limited.References were also identified from the bibliographies of identified articles and the authors5 files.Results:The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress,inhibiting the activation of fibrosis-related cells and their cytokine expression,ameliorating vascular remodeling and high blood pressure,stimulating tubular cell regeneration,as well as reducing apoptosis,autophagy,and hypertrophy.Therefore,H2S represents an alternative or additional therapeutic approach for renal fibrosis.Conclusions:We postulate that H2S may delay the occurrence and progress of renal fibrosis,thus protecting renal function.Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.

关键词： Hydrogen sulfide renal interstitial fibrosis Chronic kidney disease

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