Zhen-wu-tang ameliorates adenine-induced chronic renal failure in rats: regulation of the canonical Wnt4/beta-catenin signaling in the kidneys

La, Lei; Wang, Lili; Qin, Fei; Jiang, Jian; He, Shiming; Wang, Chunxia; Li, Yuhao

doi:10.1016/j.jep.2017.12.013

Cited by 28 publications

(18 citation statements)

References 48 publications

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“…For people who suffered from CKD, TCM has been widely used as an effective alternative therapy in China and many Asian countries. In the clinical practice, the classical Chinese herbal formulas, such as Zhenwu Decoction (La et al, 2018) and Dahuang Fuzi Decoction (Tu et al, 2014), have been widely applicated in the treatment of CKD and exerted good efficacy in alleviating symptoms, improving renal function, preventing and treating complications, and delaying the development of renal failure. However, some herbal medicines containing toxic compounds have been confirmed to exist in these formulas, for instance, Xixin, a kind of TCM which contains aristolochic acid analogs (AAAs) and is known for its nephrotoxicity (Gökmen and Lord, 2012;Michl et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Deng¹,

Yue²,

Wang

et al. 2021

Front. Pharmacol.

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Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Deng¹,

Yue²,

Wang

et al. 2021

Front. Pharmacol.

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“…Interestingly, other active compounds such as Astragaloside IV (contained in HMM) and paeoni orin (contained in PRA) with a concentration of 3.20-64.00 μg•mL − 1 were detected in SBT in our previously quality standard study [72]. Studies have experimentally proved that Astragaloside IV was able to reduce proteinuria in diabetic nephropathy mice [73] and paeoni orin could improve proteinuria in chronic renal failure rats [25]. All of the above supports our result that SBT worked against proteinuria in a multi-ingredient way.…”

Section: Discussionmentioning

confidence: 99%

“…Stephaniae Tetrandrae Radix (STR), and Chuanxiong Rhizoma (CRH). Furthermore, some single-flavor herbs or ingredients in SBT, such as Astragaloside IV of HMM, paeoniflorin of PRA, and CRH have also been revealed an exact therapeutic effect against proteinuria [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Identifying Synergistic Mechanisms of Multiple Ingredients in Shuangbai Tablets against Proteinuria by Virtual Screening and a Network Pharmacology Approach

Hao

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Shuangbai Tablets (SBT), a traditional herbal mixture, has shown substantial clinical efficacy. However, a systematic mechanism of its active ingredients and pharmacological mechanisms of action against proteinuria continues being lacking. A network pharmacology approach was effectual in discovering the relationship of multiple ingredients and targets of the herbal mixture. This study aimed to identify key targets, major active ingredients, and pathways of SBT against proteinuria by network pharmacology approach combined with thin layer chromatography (TLC). Human phenotype (HP) disease analysis, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and molecular docking were used in this study. To this end, a total of 48 candidate targets of 118 active ingredients of SBT were identified. Network analysis showed PTGS2, ESR1, and NOS2 to be the three key targets, and beta-sitosterol, quercetin, and berberine were the three major active ingredients; among them one of the major active ingredients, quercetin, was discriminated by TLC. These results of the functional enrichment analysis indicated that the most relevant disease including these 48 candidate proteins is proteinuria, SBT treated proteinuria by sympathetically regulating multiple biological pathways, such as the HIF-1, RAS, AGE-RAGE, and VEGF signaling pathways. Additionally, molecular docking validation suggested that major active ingredients of SBT were capable of binding to HIF-1A and VEGFA of the main pathways. Consequently, key targets, major active ingredients, and pathways based on data analysis of SBT against proteinuria were systematically identified confirming its utility and providing a new drug against proteinuria.

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“…Zhen Wu Tang (ZWT), a classic herbal prescription from China, has been widely used in the treatment of chronic kidney disease (CKD), including IgA nephropathy (Liu et al, 2018), adriamycin-induced nephropathy (Liang et al, 2019), and chronic glomerulonephritis (Wu et al, 2016). Previous studies on advantages of ZWT administration in CKD can mainly be documented into two sections: 1) ZWT has been widely used in the clinic in China for more than 1,000 years as a remedy for various kidney diseases as it displays efficacy in relieving symptoms manifested in the form of edema, dysuria, and oliguria (Liu et al, 2017b;La et al, 2018) and 2) fundamental studies indicate that ZWT possesses a range of bioactivities, including renoprotective, anti-inflammatory, diuretic, and antihyperlipidemic (Cai et al, 2010;Liang et al, 2014;Liu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Integrated Fecal Microbiome and Serum Metabolomics Analysis Reveals Abnormal Changes in Rats with Immunoglobulin A Nephropathy and the Intervention Effect of Zhen Wu Tang

Cao

et al. 2021

Front. Pharmacol.

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Immunoglobulin A nephropathy (IgAN), an autoimmune renal disease with complicated pathogenesis, is one of the principal reasons for end-stage renal disease in the clinic. Evidence has linked apparent alterations in the components of the microbiome and metabolome to renal disease in rats. However, thus far, there is insufficient evidence that supports the potential relationship between gut microbiome, circulating metabolites, and IgAN. This study was designed to probe the effects of IgAN on intestinal microecology and metabolic phenotypes and to understand the possible underlying mechanisms. Fecal and serum samples were collected from IgAN rats. Composition of the gut microbiota and biochemical changes in the metabolites was analyzed using 16S rDNA sequencing and untargeted metabolomics. The IgAN rats exhibited renal insufficiency and increased concentration of 24-h urine protein, in addition to deposition of IgA and IgG immune complexes in the kidney tissues. There was a disturbance in the balance of gut microbiota in IgAN rats, which was remarkably associated with renal damage. Marked changes in microbial structure and function were accompanied by apparent alterations in 1,403 serum metabolites, associated with the disorder of energy, carbohydrate, and nucleotide metabolisms. Administration of Zhen Wu Tang ameliorated microbial dysbiosis and attenuated the renal damage. Besides, treatment with Zhen Wu Tang modulated the metabolic phenotype perturbation in case of gut microbiota dysbiosis in IgAN rats. In conclusion, these findings provided a comprehensive understanding of the potential relationship between the intestinal microbiota and metabolic phenotypes in rats with IgAN. Elucidation of the intestinal microbiota composition and metabolic signature alterations could identify predictive biomarkers for disease diagnosis and progression, which might contribute to providing therapeutic strategies for IgAN.

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Zhen-wu-tang ameliorates adenine-induced chronic renal failure in rats: regulation of the canonical Wnt4/beta-catenin signaling in the kidneys

Cited by 28 publications

References 48 publications

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Identifying Synergistic Mechanisms of Multiple Ingredients in Shuangbai Tablets against Proteinuria by Virtual Screening and a Network Pharmacology Approach

Integrated Fecal Microbiome and Serum Metabolomics Analysis Reveals Abnormal Changes in Rats with Immunoglobulin A Nephropathy and the Intervention Effect of Zhen Wu Tang

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