Combinatorial Chemistry & High Throughput ScreeningCombinatorial Chemistry & High Throughput ScreeningCombinatorial Chemistry & High Throughput Screening1386-20731875-5402Bentham Science64452210.2174/0113862073260994231031070916ChemistryResearch ArticleThe Therapeutic Mechanisms of Shenyan Oral Liquid I Against Chronic Kidney Disease Based on Network Pharmacology and Experimental ValidationChengXudonginfo@benthamscience.netLiangGuoqianginfo@benthamscience.netLiuMininfo@benthamscience.netSongRujuninfo@benthamscience.netZhouLaninfo@benthamscience.netRenYaninfo@benthamscience.netHuangYuyuinfo@benthamscience.netJinWeimininfo@benthamscience.netJiangChunboinfo@benthamscience.netSuzhou TCM Hospital, Affiliated to Nanjing University of Chinese Medici, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese, Nanjing University of Traditional Chinese Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese MedicineDepartment of Nephrology, Suzhou Hospital of Traditional Chinese Medicine0110202427192885289807012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjpbr.com/1386-2073/article/view/644522

Background:Chronic Kidney Disease (CKD) leads to structural and functional abnormalities of the kidneys and seriously jeopardizes human health. Shenyan Oral Liquid (SOLI), a Chinese medicinal preparation, has been reported to protect podocytes in patients with chronic kidney disease (CKD).

Objective:The objective of this study is to investigate the mechanism of action of the Chinese medicinal preparation Senyan Oral Liquid (SOLI) in the treatment of CKD by protecting podocytes through network pharmacology technology and experimental validation.

Methods:Compounds of SOLI and targets of CKD disease were collected and screened. The SOLI network of bioactive compounds targeting CKD and the protein-protein interaction (PPI) network were constructed using Cytoscape software and the STRING online database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R software Cluster Profiler package. Molecular docking was performed using Autodock software to verify the binding ability of bioactive compounds and target genes. Subsequently, the potential mechanism of SOLI on CKD predicted by network pharmacological analysis was experimentally studied and verified in an adriamycin-induced nephropathy rat model.

Results:A total of 81 targets of SOLI components acting on CKD were identified. The results of the PPI analysis clarified that five key target genes (TNF, AKT1, IL6, VEGFA, and TP53) play a critical role in the treatment of CKD by SOLI. The GO analysis and KEGG enrichment analysis indicated that SOLI acts through multiple pathways, including the PI3K/AKT signaling pathway against CKD. Molecular docking showed that the main compounds of SOLI and five key genes had strong binding affinity. In a rat model of adriamycin-induced nephropathy, SOLI significantly ameliorated disease symptoms and improved renal histopathology. Mechanistic studies showed that SOLI upregulated the expression level of Nephrin, inhibited the PI3K/AKT pathway in renal tissues, and ultimately suppressed the activation of autophagy-related proteins in CKD.

Conclusion:SOLI exerted a renoprotective effect by regulating the Nephrin-PI3K/AKT autophagy signaling pathway, and these findings provide new ideas for the development of SOLI-based therapeutic approaches for CKD.

Shenyan oral liquid Ichronic kidney diseasetherapeutic mechanismsnetwork pharmacologyPI3K/AKT signalingautophagy.Nehus, E. Obesity and chronic kidney disease. Curr. Opin. Pediatr., 2018, 30(2), 241-246. doi: 10.1097/MOP.0000000000000586 PMID: 29346138Ruiz-Ortega, M.; Rayego-Mateos, S.; Lamas, S.; Ortiz, A.; Rodrigues-Diez, R.R. Targeting the progression of chronic kidney disease. Nat. Rev. Nephrol., 2020, 16(5), 269-288. doi: 10.1038/s41581-019-0248-y PMID: 32060481Liu, Z.H. Nephrology in China. Nat. Rev. Nephrol., 2013, 9(9), 523-528. doi: 10.1038/nrneph.2013.146 PMID: 23877587Saran, R.; Robinson, B.; Abbott, K.C.; Agodoa, L.Y.C.; Albertus, P.; Ayanian, J.; Balkrishnan, R.; Bragg-Gresham, J.; Cao, J.; Chen, J.L.T.; Cope, E.; Dharmarajan, S.; Dietrich, X.; Eckard, A.; Eggers, P.W.; Gaber, C.; Gillen, D.; Gipson, D.; Gu, H.; Hailpern, S.M.; Hall, Y.N.; Han, Y.; He, K.; Hebert, P.; Helmuth, M.; Herman, W.; Heung, M.; Hutton, D.; Jacobsen, S.J.; Ji, N.; Jin, Y.; Kalantar-Zadeh, K.; Kapke, A.; Katz, R.; Kovesdy, C.P.; Kurtz, V.; Lavallee, D.; Li, Y.; Lu, Y.; McCullough, K.; Molnar, M.Z.; Montez-Rath, M.; Morgenstern, H.; Mu, Q.; Mukhopadhyay, P.; Nallamothu, B.; Nguyen, D.V.; Norris, K.C.; O’Hare, A.M.; Obi, Y.; Pearson, J.; Pisoni, R.; Plattner, B.; Port, F.K.; Potukuchi, P.; Rao, P.; Ratkowiak, K.; Ravel, V.; Ray, D.; Rhee, C.M.; Schaubel, D.E.; Selewski, D.T.; Shaw, S.; Shi, J.; Shieu, M.; Sim, J.J.; Song, P.; Soohoo, M.; Steffick, D.; Streja, E.; Tamura, M.K.; Tentori, F.; Tilea, A.; Tong, L.; Turf, M.; Wang, D.; Wang, M.; Woodside, K.; Wyncott, A.; Xin, X.; Zeng, W.; Zepel, L.; Zhang, S.; Zho, H.; Hirth, R.A.; Shahinian, V. US renal data system 2016 annual data report: Epidemiology of kidney disease in the united states. Am. J. Kidney Dis., 2017, 69(3), A7-A8. doi: 10.1053/j.ajkd.2016.12.004 PMID: 28236831Mallett, A.; Patel, C.; Salisbury, A.; Wang, Z.; Healy, H.; Hoy, W. The prevalence and epidemiology of genetic renal disease amongst adults with chronic kidney disease in Australia. Orphanet J. Rare Dis., 2014, 9, 98. doi: 10.1186/1750-1172-9-98Breyer, M.D.; Susztak, K. Developing treatments for chronic kidney disease in the 21st century. Semin. Nephrol., 2016, 36(6), 436-447. doi: 10.1016/j.semnephrol.2016.08.001 PMID: 27987541Palmer, S.C.; Mavridis, D.; Navarese, E.; Craig, J.C.; Tonelli, M.; Salanti, G.; Wiebe, N.; Ruospo, M.; Wheeler, D.C.; Strippoli, G.F.M. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: A network meta-analysis. Lancet, 2015, 385(9982), 2047-2056. doi: 10.1016/S0140-6736(14)62459-4 PMID: 26009228Zhong, Y.; Deng, Y.; Chen, Y.; Chuang, P.Y.; Cijiang, He. J. Therapeutic use of traditional Chinese herbal medications for chronic kidney diseases. Kidney Int., 2013, 84(6), 1108-1118. doi: 10.1038/ki.2013.276 PMID: 23868014Li, X.; Wang, H. Chinese herbal medicine in the treatment of chronic kidney disease. Adv. Chronic Kidney Dis., 2005, 12(3), 276-281. doi: 10.1016/j.ackd.2005.03.007 PMID: 16010642Zhong, Y.; Menon, M.C.; Deng, Y.; Chen, Y.; He, J.C. Recent advances in traditional chinese medicine for kidney disease. Am. J. Kidney Dis., 2015, 66(3), 513-522. doi: 10.1053/j.ajkd.2015.04.013 PMID: 26015275Mao, W.; Yang, N.; Zhang, L.; Li, C.; Wu, Y.; Ouyang, W.; Xu, P.; Zou, C.; Pei, C.; Shi, W.; Zhan, J.; Yang, H.; Chen, H.; Wang, X.; Tian, Y.; Yuan, F.; Sun, W.; Xiong, G.; Chen, M.; Guan, J.; Tang, S.; Zhang, C.; Liu, Y.; Deng, Y.; Lin, Q.; Lu, F.; Hong, W.; Yang, A.; Fang, J.; Rao, J.; Wang, L.; Bao, K.; Lin, F.; Xu, Y.; Lu, Z.; Su, G. Bupi yishen formula versus losartan for non-diabetic stage 4 chronic kidney disease: A randomized controlled trial. Front. Pharmacol., 2020, 11, 627185.Chen, Y.; Deng, Y.; Ni, Z.; Chen, N.; Chen, X.; Shi, W.; Zhan, Y.; Yuan, F.; Deng, W.; Zhong, Y. Efficacy and safety of traditional chinese medicine (Shenqi particle) for patients with idiopathic membranous nephropathy: A multicenter randomized controlled clinical trial. Am. J. Kidney Dis., 2013, 62(6), 1068-1076. doi: 10.1053/j.ajkd.2013.05.005 PMID: 23810688Jiang, C.B. Clinical study of Shenyan oral liquid I on 35 cases of chronic nephritis with spleen deficiency and damp heat syndrome. Jiangsu. J. Tradit. Chin. Med., 2015, 47(10), 3.Jiang, C. B Shenyan No.1 prescription combined with western medicine in the treatment of nephrotic syndrome and its effect on coagulation indexes and immune function of patients. Shanxi. J. Tradit. Chin. Med., 2020, 41(12), 4.Jiang, C.; Liang, G.; Ren, Y.; Xu, T.; Song, Y.; Jin, W. An UPLC-MS/MS method for simultaneous quantification of the components of shenyanyihao oral solution in rat plasma. BioMed Res. Int., 2020, 2020, 4769267.Liang, G.Q.; Ji, J. Protective effect of Shenyan oral liquid I in adriamycin-induced nephropathy rats based on "Autophagy-inflammatory reaction. Tradit. Chin. Med., 2019, 37(11)Zhang, W.; Huai, Y.; Miao, Z.; Qian, A.; Wang, Y. Systems pharmacology for investigation of the mechanisms of action of traditional chinese medicine in drug discovery. Front. Pharmacol., 2019, 10, 743. doi: 10.3389/fphar.2019.00743Luo, Y.; Li, D.; Liao, Y.; Cai, C.; Wu, Q.; Ke, H.; Liu, X.; Li, H.; Hong, H.; Xu, Y.; Wang, Q.; Fang, J.; Fang, S. Systems pharmacology approach to investigate the mechanism of kai-xin-san in Alzheimer’s Disease. Front. Pharmacol., 2020, 11, 381. doi: 10.3389/fphar.2020.00381Ren, Y. Research progress and challenges of network pharmacology in the field of traditional Chinese medicine. Chin. Tradit. Herbal Drugs, 2020, 51(18), 9.Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol., 2008, 4(11), 682-690. doi: 10.1038/nchembio.118 PMID: 18936753Xu, X.; Zhang, W.; Huang, C.; Li, Y.; Yu, H.; Wang, Y.; Duan, J.; Ling, Y. A novel chemometric method for the prediction of human oral bioavailability. Int. J. Mol. Sci., 2012, 13(6), 6964-6982. doi: 10.3390/ijms13066964 PMID: 22837674Liu, H.; Wang, J.; Zhou, W.; Wang, Y.; Yang, L. Systems approaches and polypharmacology for drug discovery from herbal medicines: An example using licorice. J. Ethnopharmacol., 2013, 146(3), 773-793. doi: 10.1016/j.jep.2013.02.004 PMID: 23415946Wang, X.W.; Tian, R.M.; Yang, Y.Q.; Wang, K.; Li, E.N.; Han, X.D.; Bao, K.; Mao, W.; Xu, H.T.; Liu, B.; Xu, P. Tripterygium glycoside fraction n2 ameliorates adriamycin-induced nephrotic syndrome in rats by suppressing apoptosis. J. Ethnopharmacol., 2020, 257, 112789. doi: 10.1016/j.jep.2020.112789Jiang, C.B.; Wei, M.G.; Tu, Y.; Zhu, H.; Li, C.Q.; Jing, W.M.; Sun, W. Triptolide attenuates podocyte injury by regulating expression of miRNA-344b-3p and miRNA-30b-3p in rats with adriamycin-induced nephropathy. Evid. Based Complement. Alternat. Med., 2015, 2015, 107814. doi: 10.1155/2015/107814Yin, L.; Mao, Y.; Song, H.; Wang, Y.; Zhou, W.; Zhang, Z. Vincristine alleviates adriamycin-induced nephropathy through stabilizing actin cytoskeleton. Cell Biosci., 2017, 7(1) doi: 10.1186/s13578-016-0129-zCarbon, S.; Douglass, E.; Good, B.M.; Unni, D.R.; Harris, N.L.; Mungall, C.J.; Basu, S.; Chisholm, R.L.; Dodson, R.J.; Hartline, E.; Fey, P.; Thomas, P.D.; Albou, L-P.; Ebert, D.; Kesling, M.J.; Mi, H.; Muruganujan, A.; Huang, X.; Mushayahama, T.; LaBonte, S.A.; Siegele, D.A.; Antonazzo, G.; Attrill, H.; Brown, N.H.; Garapati, P.; Marygold, S.J.; Trovisco, V.; dos Santos, G.; Falls, K.; Tabone, C.; Zhou, P.; Goodman, J.L.; Strelets, V.B.; Thurmond, J.; Garmiri, P.; Ishtiaq, R.; Rodríguez-López, M.; Acencio, M.L.; Kuiper, M.; Lægreid, A.; Logie, C.; Lovering, R.C.; Kramarz, B.; Saverimuttu, S.C.C.; Pinheiro, S.M.; Gunn, H.; Su, R.; Thurlow, K.E.; Chibucos, M.; Giglio, M.; Nadendla, S.; Munro, J.; Jackson, R.; Duesbury, M.J.; Del-Toro, N.; Meldal, B.H.M.; Paneerselvam, K.; Perfetto, L.; Porras, P.; Orchard, S.; Shrivastava, A.; Chang, H-Y.; Finn, R.D.; Mitchell, A.L.; Rawlings, N.D.; Richardson, L.; Sangrador-Vegas, A.; Blake, J.A.; Christie, K.R.; Dolan, M.E.; Drabkin, H.J.; Hill, D.P.; Ni, L.; Sitnikov, D.M.; Harris, M.A.; Oliver, S.G.; Rutherford, K.; Wood, V.; Hayles, J.; Bähler, J.; Bolton, E.R.; De Pons, J.L.; Dwinell, M.R.; Hayman, G.T.; Kaldunski, M.L.; Kwitek, A.E.; Laulederkind, S.J.F.; Plasterer, C.; Tutaj, M.A.; Vedi, M.; Wang, S-J.; D’Eustachio, P.; Matthews, L.; Balhoff, J.P.; Aleksander, S.A.; Alexander, M.J.; Cherry, J.M.; Engel, S.R.; Gondwe, F.; Karra, K.; Miyasato, S.R.; Nash, R.S.; Simison, M.; Skrzypek, M.S.; Weng, S.; Wong, E.D.; Feuermann, M.; Gaudet, P.; Morgat, A.; Bakker, E.; Berardini, T.Z.; Reiser, L.; Subramaniam, S.; Huala, E.; Arighi, C.N.; Auchincloss, A.; Axelsen, K.; Argoud-Puy, G.; Bateman, A.; Blatter, M-C.; Boutet, E.; Bowler, E.; Breuza, L.; Bridge, A.; Britto, R.; Bye-A-Jee, H.; Casas, C.C.; Coudert, E.; Denny, P.; Estreicher, A.; Famiglietti, M.L.; Georghiou, G.; Gos, A.; Gruaz-Gumowski, N.; Hatton-Ellis, E.; Hulo, C.; Ignatchenko, A.; Jungo, F.; Laiho, K.; Le Mercier, P.; Lieberherr, D.; Lock, A.; Lussi, Y.; MacDougall, A.; Magrane, M.; Martin, M.J.; Masson, P.; Natale, D.A.; Hyka-Nouspikel, N.; Orchard, S.; Pedruzzi, I.; Pourcel, L.; Poux, S.; Pundir, S.; Rivoire, C.; Speretta, E.; Sundaram, S.; Tyagi, N.; Warner, K.; Zaru, R.; Wu, C.H.; Diehl, A.D.; Chan, J.N.; Grove, C.; Lee, R.Y.N.; Muller, H-M.; Raciti, D.; Van Auken, K.; Sternberg, P.W.; Berriman, M.; Paulini, M.; Howe, K.; Gao, S.; Wright, A.; Stein, L.; Howe, D.G.; Toro, S.; Westerfield, M.; Jaiswal, P.; Cooper, L.; Elser, J. The Gene Ontology resource: Enriching a Gold mine. Nucleic Acids Res., 2021, 49(D1), D325-D334. doi: 10.1093/nar/gkaa1113 PMID: 33290552Kanehisa, M.; Sato, Y.; Kawashima, M.; Furumichi, M.; Tanabe, M. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res., 2016, 44(D1), D457-D462. doi: 10.1093/nar/gkv1070 PMID: 26476454Wang, Y.; Feng, Y.; Li, M.; Yang, M.; Shi, G.; Xuan, Z.; Yin, D.; Xu, F. Traditional chinese medicine in the treatment of chronic kidney diseases: Theories, applications, and mechanisms. Front. Pharmacol., 2022, 13, 917975. doi: 10.3389/fphar.2022.917975 PMID: 35924053Qi, Z.Q. Application of dispelling discharge in the treatment of chronic kidney disease with damp-heat syndrome. Tradit. Chin. Med., 2018, 33(05), 4.Kma, L.; Baruah, T.J. The interplay of ROS and the PI3K/Akt pathway in autophagy regulation. Biotechnol. Appl. Biochem., 2022, 69(1), 248-264. doi: 10.1002/bab.2104 PMID: 33442914Yin, H.; Zuo, Z.; Yang, Z.; Guo, H.; Fang, J.; Cui, H.; Ouyang, P.; Chen, X.; Chen, J.; Geng, Y.; Chen, Z.; Huang, C.; Zhu, Y. Nickel induces autophagy via PI3K/AKT/mTOR and AMPK pathways in mouse kidney. Ecotoxicol. Environ. Saf., 2021, 223, 112583.Inker, L.A.; Levey, A.S.; Coresh, J. Estimated glomerular filtration rate from a panel of filtration markers—hope for increased accuracy beyond measured glomerular filtration rate? Adv. Chronic Kidney Dis., 2018, 25(1), 67-75. doi: 10.1053/j.ackd.2017.10.004 PMID: 29499889Patrakka, J.; Tryggvason, K. New insights into the role of podocytes in proteinuria. Nat. Rev. Nephrol., 2009, 5(8), 463-468. doi: 10.1038/nrneph.2009.108 PMID: 19581907Matsusaka, T.; Sandgren, E.; Shintani, A.; Kon, V.; Pastan, I.; Fogo, A.B.; Ichikawa, I. Podocyte injury damages other podocytes. J. Am. Soc. Nephrol., 2011, 22(7), 1275-1285. doi: 10.1681/ASN.2010090963 PMID: 21719786Sanajou, D.; Ghorbani Haghjo, A.; Argani, H.; Roshangar, L.; Ahmad, S.N.S.; Jigheh, Z.A.; Aslani, S.; Panah, F.; Rashedi, J.; Mesgari Abbasi, M. FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced diabetic rats. J. Physiol. Biochem., 2018, 74(3), 467-478. doi: 10.1007/s13105-018-0640-2 PMID: 29948786Yang, Z.; Klionsky, D.J. Eaten alive: A history of macroautophagy. Nat. Cell Biol., 2010, 12(9), 814-822. doi: 10.1038/ncb0910-814 PMID: 20811353Asanuma, K.; Tanida, I.; Shirato, I.; Ueno, T.; Takahara, H.; Nishitani, T.; Kominami, E.; Tomino, Y. MAP‐LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis. FASEB J., 2003, 17(9), 1165-1167. doi: 10.1096/fj.02-0580fje PMID: 12709412Song, Z.; Guo, Y.; Zhou, M.; Zhang, X. The PI3K/p-Akt signaling pathway participates in calcitriol ameliorating podocyte injury in DN rats. Metabolism, 2014, 63(10), 1324-1333. doi: 10.1016/j.metabol.2014.06.013 PMID: 25044177Liu, N.; Xu, L.; Shi, Y.; Zhuang, S. Podocyte autophagy: A potential therapeutic target to prevent the progression of diabetic nephropathy. J. Diabetes Res., 2017, 2017, 3560238. doi: 10.1155/2017/3560238Yu, Z.K.; Yang, B.; Zhang, Y.; Li, L.S.; Zhao, J.N.; Hao, W. Modified Huangqi Chifeng decoction inhibits excessive autophagy to protect against Doxorubicin induced nephrotic syndrome in rats via the PI3K/mTOR signaling pathway. Exp. Ther. Med., 2018, 16(3), 2490-2498. doi: 10.3892/etm.2018.6492 PMID: 30210600Hemmings, B.A.; Restuccia, D.F. PI3K-PKB/Akt pathway. Cold Spring Harb. Perspect. Biol., 2012, 4(9), a011189. doi: 10.1101/cshperspect.a011189 PMID: 22952397Yu, S.; Ren, Q.; Chen, J.; Huang, J.; Liang, R. Rapamycin reduces podocyte damage by inhibiting the PI3K/AKT/mTOR signaling pathway and promoting autophagy. Eur. J. Inflamm., 2022, 20, 1721727X221081732.Huber, T.B.; Hartleben, B.; Kim, J.; Schmidts, M.; Schermer, B.; Keil, A.; Egger, L.; Lecha, R.L.; Borner, C.; Pavenstädt, H.; Shaw, A.S.; Walz, G.; Benzing, T. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol. Cell. Biol., 2003, 23(14), 4917-4928. doi: 10.1128/MCB.23.14.4917-4928.2003 PMID: 12832477Lu, H.; Yao, H.; Zou, R.; Chen, X.; Xu, H. Galangin suppresses renal inflammation via the inhibition of NF-kappaB, PI3K/AKT and NLRP3 in uric acid treated NRK-52E tubular epithelial cells. BioMed Res. Int., 2019, 2019, 3018357.Ni, W.J.; Zhou, H.; Ding, H.H.; Tang, L.Q. Berberine ameliorates renal impairment and inhibits podocyte dysfunction by targeting the phosphatidylinositol 3‐kinase–protein kinase B pathway in diabetic rats. J. Diabetes Investig., 2020, 11(2), 297-306. doi: 10.1111/jdi.13119 PMID: 31336024Huber, T.B.; Köttgen, M.; Schilling, B.; Walz, G.; Benzing, T. Interaction with podocin facilitates nephrin signaling. J. Biol. Chem., 2001, 276(45), 41543-41546. doi: 10.1074/jbc.C100452200 PMID: 11562357