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Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, so there is an urgent need to suppress its development at early stage. Shenkang pills (SKP) are a hospital prescription selected and optimized from effective traditional Chinese medicinal formulas for clinical treatment of DN...

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Autores principales: Wang, Fujing, Fan, Jia’er, Pei, Tingting, He, Zhuo’en, Zhang, Jiaxing, Ju, Liliang, Han, Zhongxiao, Wang, Mingqing, Xiao, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8873791/
https://www.ncbi.nlm.nih.gov/pubmed/35222021
http://dx.doi.org/10.3389/fphar.2022.781806
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author Wang, Fujing
Fan, Jia’er
Pei, Tingting
He, Zhuo’en
Zhang, Jiaxing
Ju, Liliang
Han, Zhongxiao
Wang, Mingqing
Xiao, Wei
author_facet Wang, Fujing
Fan, Jia’er
Pei, Tingting
He, Zhuo’en
Zhang, Jiaxing
Ju, Liliang
Han, Zhongxiao
Wang, Mingqing
Xiao, Wei
author_sort Wang, Fujing
collection PubMed
description Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, so there is an urgent need to suppress its development at early stage. Shenkang pills (SKP) are a hospital prescription selected and optimized from effective traditional Chinese medicinal formulas for clinical treatment of DN. In the present study, liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-Q-TOF-MS) and total contents qualification were applied to generate a quality control standard of SKP. For verifying the therapeutic effects of SKP, db/db mice were administered intragastrically with SKP at a human-equivalent dose (1.82 g/kg) for 4 weeks. Moreover, the underlying mechanism of SKP were analyzed by the renal RNA sequencing and network pharmacology. LC-Q-TOF-MS identified 46 compounds in SKP. The total polysaccharide and organic acid content in SKP were 4.60 and 0.11 mg/ml, respectively, while the total flavonoid, saponin, and protein content were 0.25, 0.31, and 0.42 mg/ml, respectively. Treatment of SKP significantly reduced fasting blood glucose, improved renal function, and ameliorated glomerulosclerosis and focal foot processes effacement in db/db mice. In addition, SKP protected podocytes from injury by increasing nephrin and podocin expression. Furthermore, transcriptome analyses revealed that 430 and 288 genes were up and down-regulated in mice treated with SKP, relative to untreated controls. Gene ontology enrichment analysis revealed that the differentially expressed genes mainly involved in modulation of cell division and chromosome segregation. Weighted gene co-expression network analysis and network pharmacology analysis indicated that aurora kinase B (AURKB), Rac GTPase activating protein 1 (RacGAP1) and SHC binding, and spindle associated 1 (shcbp1) might be the core targets of SKP. This protein and Ras homolog family member A (RhoA) were found overexpression in db/db mice, but significantly decreased with SKP treatment. We conclude that SKP can effectively treat early-stage DN and improve renal podocyte dysfunction. The mechanism may involve down-regulation of the AURKB/RacGAP1/RhoA pathway.
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spelling pubmed-88737912022-02-26 Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway Wang, Fujing Fan, Jia’er Pei, Tingting He, Zhuo’en Zhang, Jiaxing Ju, Liliang Han, Zhongxiao Wang, Mingqing Xiao, Wei Front Pharmacol Pharmacology Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, so there is an urgent need to suppress its development at early stage. Shenkang pills (SKP) are a hospital prescription selected and optimized from effective traditional Chinese medicinal formulas for clinical treatment of DN. In the present study, liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-Q-TOF-MS) and total contents qualification were applied to generate a quality control standard of SKP. For verifying the therapeutic effects of SKP, db/db mice were administered intragastrically with SKP at a human-equivalent dose (1.82 g/kg) for 4 weeks. Moreover, the underlying mechanism of SKP were analyzed by the renal RNA sequencing and network pharmacology. LC-Q-TOF-MS identified 46 compounds in SKP. The total polysaccharide and organic acid content in SKP were 4.60 and 0.11 mg/ml, respectively, while the total flavonoid, saponin, and protein content were 0.25, 0.31, and 0.42 mg/ml, respectively. Treatment of SKP significantly reduced fasting blood glucose, improved renal function, and ameliorated glomerulosclerosis and focal foot processes effacement in db/db mice. In addition, SKP protected podocytes from injury by increasing nephrin and podocin expression. Furthermore, transcriptome analyses revealed that 430 and 288 genes were up and down-regulated in mice treated with SKP, relative to untreated controls. Gene ontology enrichment analysis revealed that the differentially expressed genes mainly involved in modulation of cell division and chromosome segregation. Weighted gene co-expression network analysis and network pharmacology analysis indicated that aurora kinase B (AURKB), Rac GTPase activating protein 1 (RacGAP1) and SHC binding, and spindle associated 1 (shcbp1) might be the core targets of SKP. This protein and Ras homolog family member A (RhoA) were found overexpression in db/db mice, but significantly decreased with SKP treatment. We conclude that SKP can effectively treat early-stage DN and improve renal podocyte dysfunction. The mechanism may involve down-regulation of the AURKB/RacGAP1/RhoA pathway. Frontiers Media S.A. 2022-02-11 /pmc/articles/PMC8873791/ /pubmed/35222021 http://dx.doi.org/10.3389/fphar.2022.781806 Text en Copyright © 2022 Wang, Fan, Pei, He, Zhang, Ju, Han, Wang and Xiao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wang, Fujing
Fan, Jia’er
Pei, Tingting
He, Zhuo’en
Zhang, Jiaxing
Ju, Liliang
Han, Zhongxiao
Wang, Mingqing
Xiao, Wei
Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway
title Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway
title_full Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway
title_fullStr Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway
title_full_unstemmed Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway
title_short Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway
title_sort effects of shenkang pills on early-stage diabetic nephropathy in db/db mice via inhibiting aurkb/racgap1/rhoa signaling pathway
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8873791/
https://www.ncbi.nlm.nih.gov/pubmed/35222021
http://dx.doi.org/10.3389/fphar.2022.781806
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