Tetrandrine mediates renal function and redox homeostasis in a streptozotocin-induced diabetic nephropathy rat model through Nrf2/HO-1 reactivation

Su, Luyu; Cao, Ping; Wang, Haiyan

doi:10.21037/atm-20-5548

Cited by 28 publications

(13 citation statements)

References 36 publications

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“…Tetrandrine has been reported to possess extensive pharmacological properties including anticancer ( 39 ), anti-inflammation ( 40 , 41 ), immunomodulatory effects ( 42 ), and regulates several important biological processes in the pathogenesis of kidney diseases. Tetrandrine could alleviate podocyte injury induced by TRPC6 overexpression ( 43 ), decrease 24 h urine protein and glomerular cell proliferation in the membranous glomerulopathy ( 44 ), and restrain diabetic process and renal damage in diabetic nephropathy ( 45 ). Early studies have shown that tetrandrine could inhibit the activation of mesangial cells by down-regulating the ERK/ NF-κB signaling pathway ( 46 ), suggesting a protective effect on the pathological proliferated mesangial cells mediated renal damage.…”

Section: Discussionmentioning

confidence: 99%

Identification of Hub Genes and Therapeutic Agents for IgA Nephropathy Through Bioinformatics Analysis and Experimental Validation

Xia

Liu

et al. 2022

Front. Med.

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BackgroundIgA nephropathy (IgAN) is the most common primary glomerular disease and the leading cause of the end-stage renal disease in the world. The pathogenesis of IgAN has not been well elucidated, and yet treatment is limited. High-throughput microarray has been applied for elucidating molecular biomarkers and potential mechanisms involved in IgAN. This study aimed to identify the potential key genes and therapeutics associated with IgAN using integrative bioinformatics and transcriptome-based computational drug repurposing approach.MethodsThree datasets of mRNA expression profile were obtained from the gene expression omnibus database and differentially expressed genes (DEGs) between IgAN glomeruli and normal tissue were identified by integrated analysis. Gene ontology and pathway enrichment analyses of the DEGs were performed by R software, and protein-protein interaction networks were constructed using the STRING online search tool. External dataset and immunohistochemical assessment of kidney biopsy specimens were used for hub gene validation. Potential compounds for IgAN therapy were obtained by Connectivity Map (CMap) analysis and preliminarily verified in vitro. Stimulated human mesangial cells were collected for cell proliferation and cell cycle analysis using cell counting kit 8 and flow cytometry, respectively.Results134 DEGs genes were differentially expressed across kidney transcriptomic data from IgAN patients and healthy living donors. Enrichment analysis showed that the glomerular compartments underwent a wide range of interesting pathological changes during kidney injury, focused on anion transmembrane transporter activity and protein digestion and absorption mostly. Hub genes (ITGB2, FCER1G, CSF1R) were identified and verified to be significantly upregulated in IgAN patients, and associated with severity of renal lesions. Computational drug repurposing with the CMap identified tetrandrine as a candidate treatment to reverse IgAN hub gene expression. Tetrandrine administration significantly reversed mesangial cell proliferation and cell cycle transition.ConclusionThe identification of DEGs and related therapeutic strategies of IgAN through this integrated bioinformatics analysis provides a valuable resource of therapeutic targets and agents of IgAN. Especially, our findings suggest that tetrandrine might be beneficial for IgAN, which deserves future research.

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Section: Discussionmentioning

confidence: 99%

Identification of Hub Genes and Therapeutic Agents for IgA Nephropathy Through Bioinformatics Analysis and Experimental Validation

Xia

Liu

et al. 2022

Front. Med.

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“…TP53 and VEGFA are also important molecules that act as important roles in renal microangiogenesis and maintain the functions of kidney [ 40 , 41 ]. In addition, tetrandrine can reduce the levels of inflammatory factors TNF- α and IL-6 and elevate IL-10 level in rats with diabetic nephropathy (DN) [ 42 ]. Calycosin also can ameliorate diabetes-induced renal inflammation as indicated by the reduced TNF- α level [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology and In Vivo Experimental Validation to Uncover the Renoprotective Mechanisms of Fangji Huangqi Decoction on Nephrotic Syndrome

Yin

Mao

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Fangji Huangqi decoction (FHD) is a traditional Chinese medicine formula that has the potential efficacy for nephrotic syndrome (NS) treatment. This study aims to explore the effects and underlying mechanisms of FHD against NS via network pharmacology and in vivo experiments. Methods. The bioactive compounds and targets of FHD were retrieved from the TCMSP database. NS-related targets were collected from GeneCards and DisGeNET databases. The compound-target and protein-protein interaction networks were constructed by Cytoscape 3.8 and BisoGenet, respectively. GO and KEGG analyses were performed by the DAVID online tool. The interactions between active compounds and hub genes were revealed by molecular docking. An NS rat model was established to validate the renoprotective effects and molecular mechanisms of FHD against NS in vivo. Results. A total of 32 hub genes were predicted to play essential roles in FHD treating NS. Eight main bioactive compounds of FHD had the good affinity with 9 hub targets (CCL2, IL-10, PTGS2, TNF, MAPK1, IL-6, CXCL8, TP53, and VEGFA). The therapeutic effect of FHD on NS was closely involved in the regulation of inflammation and PI3K-Akt pathway. In vivo experiments confirmed the renoprotective effect of FHD on NS, evidenced by reducing the levels of proteinuria, serum creatinine, blood urea nitrogen, and inflammatory factors in NS rats. The PI3K activator 740Y-P weakened the effects of FHD against NS. Furthermore, FHD downregulated the levels of PTGS2, MAPK1, IL-6, and p-Akt in NS rats. Conclusions. FHD alleviates kidney injury and inflammation in NS by targeting PTGS2, MAPK1, IL-6, and PI3K-Akt pathway.

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“…NRF2 regulates OS-induced pyroptosis via heme oxygenase-1 (HO-1), an antioxidant enzyme that is involved in regulating antioxidant and anti-inflammatory responses in cells. 14 In vitro studies 15 , 16 have confirmed that the NRF2/HO-1 regulatory pathway is of key significance in the occurrence and development of DN. Metastasis-related lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved long noncoding RNA (lncRNA) that has been found to be associated with pyroptosis in DM.…”

Section: Introductionmentioning

confidence: 92%

Atorvastatin Regulates MALAT1/miR-200c/NRF2 Activity to Protect Against Podocyte Pyroptosis Induced by High Glucose

Zuo¹,

Chen²,

He³

et al. 2021

DMSO

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Background Diabetic nephropathy (DN) is one of the main complications of diabetes mellitus (DM), which leads to the long-term loss of kidney functions. Long noncoding RNAs (LncRNAs) can alleviate DN by interacting with microRNAs (miRNAs). In this work, we aimed to explore the effects of the MALAT1/miR-200c/NRF2 regulatory axis on the pyroptosis and oxidative stress (Oxidative stress, OS) of renal podocytes in high glucose (HG) environment and whether the lipid-lowering drug atorvastatin (AT) can relieve renal OS through this approach. Methods MPC-5, a mouse podocyte cell line, was induced by HG as a cell model. The protein expressions of caspase-1, GSDMD, NLRP3, NRF2, etc. were detected by Western blotting and immunofluorescence, and the mRNA level of caspase-1, GSDMD, NLRP3, NRF2, MALAT1, miR-200c was tested by qRT-PCR. The cell pyroptosis of podocytes treated with AT was verified by CCK-8 or flow cytometry. The levels of Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were measured by spectrophotometer, respectively. Results The caspase-1 was upregulated in time-dependent manner and got the peak at 48 h and 30 mmol/L respectively in MPC-5 cells treated with HG. Further, the expression of GSDMD, MALAT1 and miR-200c were increased, while the level of NRF2, HO-1, OS-related indicators, were decreased simultaneously. Knockdown the MALAT1 protected MPC-5 cells from pyroptosis and OS induced by HG. However, overexpressing miR-200c in control-group cells increased pyroptosis and upregulated the OS level with HG culture medium. Further, atorvastatin protected MPC-5 cells from cell pyroptosis and downregulated the level of renal OS via attenuating the expression of MALAT1 and miR-200c. Conclusion Atorvastatin protects podocyte cells via MALAT1/miR-200c/NRF2 signal pathway from pyroptosis and OS induced by HG.

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Tetrandrine mediates renal function and redox homeostasis in a streptozotocin-induced diabetic nephropathy rat model through Nrf2/HO-1 reactivation

Cited by 28 publications

References 36 publications

Identification of Hub Genes and Therapeutic Agents for IgA Nephropathy Through Bioinformatics Analysis and Experimental Validation

Identification of Hub Genes and Therapeutic Agents for IgA Nephropathy Through Bioinformatics Analysis and Experimental Validation

Network Pharmacology and In Vivo Experimental Validation to Uncover the Renoprotective Mechanisms of Fangji Huangqi Decoction on Nephrotic Syndrome

Atorvastatin Regulates MALAT1/miR-200c/NRF2 Activity to Protect Against Podocyte Pyroptosis Induced by High Glucose

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