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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2023

Open Access 01-12-2023 | Hypertension | Research

2-phenylacetamide Separated from the seed of Lepidium apetalum Willd. inhibited renal fibrosis via MAPK pathway mediated RAAS and oxidative stress in SHR Rats

Authors: Pei-pei Yuan, Meng Li, Qi Zhang, Meng-nan Zeng, Ying-ying Ke, Ya-xin Wei, Yang Fu, Xiao-ke Zheng, Wei-sheng Feng

Published in: BMC Complementary Medicine and Therapies | Issue 1/2023

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Abstract

Background

Renal fibrosis with Renin–angiotensin–aldosterone system (RAAS) activation and oxidative stress are one of the major complications in hypertension. 2-phenylacetamide (PA), a major active component of Lepidium apetalum Willd. (L.A), has numerous pharmacological effects. Its analogues have the effect of anti-renal fibrosis and alleviating renal injury. This study aims to explore the underlying mechanism of PA for regulating the renal fibrosis in SHR based on the MAPK pathway mediated RAAS and oxidative stress.

Methods

The SHR rats were used as the hypertension model, and the WKY rats were used as the control group. The blood pressure (BP), urine volume were detected every week. After PA treatment for 4 weeks, the levels of RAAS, inflammation and cytokines were measured by Enzyme-Linked Immunosorbnent Assay (ELISA). Hematoxylin–Eosin staining (HE), Masson and Immunohistochemistry (IHC) were used to observe the renal pathology, collagen deposition and fibrosis. Western blot was used to examine the MAPK pathway in renal. Finally, the SB203580 (p38 MAPK inhibitor) antagonism assay in the high NaCl-induced NRK52e cells was used, together with In-Cell Western (ICW), Flow Cytometry (FCM), High Content Screening (HCS) and ELISA to confirm the potential pharmacological mechanism.

Results

PA reduced the BP, RAAS, inflammation and cytokines, promoted the urine, and relieved renal pathological injury and collagen deposition, repaired renal fibrosis, decreased the expression of NADPH Oxidase 4 (NOX4), transforming growth factor-β (TGF-β), SMAD3 and MAPK signaling pathway in SHR rats. Meanwhile,,the role of PA could be blocked by p38 antagonist SB203580 effectively in the high NaCl-induced NRK52e cells. Moreover, molecular docking indicated that PA occupied the ligand binding sites of p38 MAPK.

Conclusion

PA inhibited renal fibrosis via MAPK signalling pathway mediated RAAS and oxidative stress in SHR Rats.
Appendix
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Literature
1.
Wan N, Rahman A, Nishiyama A. Esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker (MRB) in hypertension and chronic kidney disease. J Hum Hypertens. 2021;35(2):148–56.CrossRefPubMed
2.
Hu B, Song J, Ji X, Liu Z, Cong M, Liu D. Sodium ferulate protects against Angiotensin II-induced cardiac hypertrophy in mice by regulating the MAPK/ERK and JNK pathways. Biomed Res Int. 2017;2017:3754942.CrossRefPubMedPubMedCentral
3.
Yegorov Y, Poznyak A, Nikiforov N, Sobenin I, Orekhov A. The link between chronic stress and accelerated aging. Biomedicines. 2020; 8(7):198.
4.
Alshahrani S. Aliskiren - A promising antioxidant agent beyond hypertension reduction. Chem Biol Interact. 2020;326: 109145.CrossRefPubMed
5.
de Almeida AA-O, de Almeida Rezende MA-O, Dantas SA-O, de Lima Silva SA-O, de Oliveira JA-O, de Lourdes Assunção Araújo de Azevedo F, Alves RA-O, de Menezes GMS, Dos Santos PF, Gonçalves TA-OX, et al. Unveiling the role of inflammation and oxidative stress on age-related cardiovascular diseases. Oxid Med Cell Longev. 2020; (1942–0994 (Electronic)):1954398.
6.
Zhang Y, Wei W, Shilova V, Petrashevskaya NN, Zernetkina VI, Grigorova YN, Marshall CA, Fenner RC, Lehrmann E, Wood WH, 3rd, et al. Monoclonal antibody to marinobufagenin downregulates TGFβ profibrotic signaling in left ventricle and kidney and reduces tissue remodeling in salt-sensitive hypertension. J Am Heart Assoc. 2019;8(20):e012138.
7.
Xu N, Jiang S, Persson P, Persson E, Lai E, Patzak A. Reactive oxygen species in renal vascular function. Acta Physiol (Oxf). 2020;229(4): e13477.CrossRefPubMed
8.
Li M, Zeng M, Zhang Z, Zhang J, Zhang B, Zhao X, Zheng X, Feng W. Uridine derivatives from the seeds of Lepidium apetalum Willd. and their estrogenic effects. Phytochemistry. 2018; 155:45–52.
9.
Wang S, Shi P, Qu L, Ruan J, Yang S, Yu H, Zhang Y, Wang T: Bioactive constituents obtained from the Seeds of Lepidium apetalum Willd. Molecules (Basel, Switzerland) 2017; 22(4):540.
10.
Xu W, Chu K, Li H, Chen L, Zhang Y, Tang X. Extraction of Lepidium apetalum seed oil using supercritical carbon dioxide and anti-oxidant activity of the extracted oil. Molecules (Basel, Switzerland). 2011;16(12):10029–45.CrossRefPubMed
11.
Zhou X-d, Tang L-y, Zhou G-h, Kou Z-z, Wang T, Wang Z-j: Advances on Lepidii Semen and Descurainiae Semen. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 2014; 39(24):4699–4708.
12.
Wei-sheng F, Zhi-guang Z, Meng L, Jing-ke Z, Xuan Z, Xiao-ke Z, Hai-xue K. Chemical constituents from the seeds of Lepidium apetalum willd. Chin Pharm J. 2018;53(01):16–9.
13.
Tabacova S, Kimmel CA, Wall K, Hansen D. Atenolol developmental toxicity: animal-to-human comparisons. Birth Defects Res A. 2003;67(3):181–92.CrossRef
14.
Li D, Cheng S, Wei D, Ren Y, Zhang D. Production of enantiomerically pure (S)-beta-phenylalanine and (R)-beta-phenylalanine by penicillin G acylase from Escherichia coli in aqueous medium. Biotech Lett. 2007;29(12):1825–30.CrossRef
15.
Nielsen FS, Rossing P, Gall MA, Skott P, Smidt UM, Parving HH. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes. 1997;46(7):1182–8.CrossRefPubMed
16.
Liao L, Yan Y-M, Xu T, Xia H-L, Cheng Y-X. A pair of novel sulfonyl-containing N-acetyldopamine dimeric enantiomers from Aspongopus chinensis. Nat Prod Commun. 2020;15(3):1-5.
17.
Zhang Q, Yuan P, Li M, Fu Y, Hou Y, Sun Y, Gao L, Wei Y, Feng W, Zheng X. Effect of phenylacetamide isolated from lepidium apetalum on myocardial injury in spontaneously hypertensive rats and its possible mechanism. Pharm Biol. 2020;58(1):597–609.CrossRefPubMedPubMedCentral
18.
Yuan P, Zheng X, Li M, Ke Y, Fu Y, Zhang Q, Wang X, Feng W. Two sulfur glycoside compounds isolated from Lepidium apetalum willd protect NRK52e cells against hypertonic-induced adhesion and inflammation by suppressing the MAPK signaling pathway and RAAS. Molecules. 2017;22(11):1956–70.CrossRefPubMedPubMedCentral
19.
Zeng M, Li M, Li M, Zhang B, Li B, Zhang L, Feng W, Zheng X. 2-Phenylacetamide isolated from the seeds of Lepidium apetalum and its estrogen-like effects In Vitro and In Vivo. Molecules (Basel, Switzerland) 2018; 23(9):2293.
20.
Alevy Y, Patel A, Romero A, Patel D, Tucker J, Roswit W, Miller C, Heier R, Byers D, Brett T, et al. IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. J Clin Investig. 2012;122(12):4555–68.CrossRefPubMedPubMedCentral
21.
22.
Balakumar P, Sambathkumar R, Mahadevan N, Muhsinah A, Alsayari A, Venkateswaramurthy N, Jagadeesh G. A potential role of the renin-angiotensin-aldosterone system in epithelial-to-mesenchymal transition-induced renal abnormalities: mechanisms and therapeutic implications. Pharmacol Res. 2019;146: 104314.CrossRefPubMed
23.
Wang J, Yang Q, Yang C, Cai Y, Xing T, Gao L, Wang F, Chen X, Liu X, He X, et al. Smad3 promotes AKI sensitivity in diabetic mice via interaction with p53 and induction of NOX4-dependent ROS production. Redox Biol. 2020;32: 101479.CrossRefPubMedPubMedCentral
24.
Alyaseer A, de Lima M, Braga T. The Role of NLRP3 Inflammasome activation in the epithelial to Mesenchymal transition process during the fibrosis. Front Immunol. 2020;11:883.CrossRefPubMedPubMedCentral
25.
Jha JC, Dai A, Garzarella J, Charlton A, Urner S, Østergaard JA, Okabe J, Holterman CE, Skene A, Power DA, et al. Independent of Renox, NOX5 promotes renal inflammation and fibrosis in diabetes by activating ROS-sensitive pathways. Diabetes. 2022;71(6):1282–98.CrossRefPubMed
26.
Chen Z, Sun X, Li X, Xu Z, Yang Y, Lin Z, Xiao H, Zhang M, Quan S, Huang H. Polydatin attenuates renal fibrosis in diabetic mice through regulating the Cx32-Nox4 signaling pathway. Acta Pharmacol Sin. 2020;41(12):1587–96.CrossRefPubMedPubMedCentral
27.
Nistala R, Meuth A, Smith C, An J, Habibi J, Hayden M, Johnson M, Aroor A, Whaley-Connell A, Sowers J, et al. DPP4 inhibition mitigates ANG II-mediated kidney immune activation and injury in male mice. Am J Physiol Renal Physiol. 2021;320(3):F505–17.CrossRefPubMedPubMedCentral
28.
Fatima N, Patel S, Hussain T: Angiotensin II Type 2 Receptor: A target for protection against hypertension, metabolic dysfunction, and organ remodeling. Hypertension (Dallas, Tex : 1979). 2021; 77(6):1845–1856.
29.
Assersen K, Sumners C, Steckelings U. The renin-angiotensin system in hypertension, a constantly renewing classic: focus on the Angiotensin AT-Receptor. Can J Cardiol. 2020;36(5):683–93.CrossRefPubMed
30.
Yoon J, Lee H, Kim H, Han B, Lee H, Lee Y, Kang D. Sauchinone protects renal mesangial cell dysfunction against angiotensin II by improving renal fibrosis and inflammation. Int J Mol Sci. 2020, 21(19):7003.
31.
Dixon D, Wohlford G, Abbate A. Inflammation and hypertension: Causal or Not? Hypertension (Dallas, Tex : 1979). 2020; 75(2):297–298.
32.
Kurtzeborn K, Kwon H, Kuure S. MAPK/ERK signaling in regulation of renal differentiation. Int J Mol Sci. 2019; 20(7):1779.
33.
Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda A. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell. 1994;78(6):1027–37.CrossRefPubMed
34.
Han J, Lee J, Bibbs L, Ulevitch R. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science (New York, NY). 1994;265(5173):808–11.CrossRef
35.
Lee J, Laydon J, McDonnell P, Gallagher T, Kumar S, Green D, McNulty D, Blumenthal M, Heys J, Landvatter S, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372(6508):739–46.CrossRefPubMed
36.
Freshney N, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994;78(6):1039–49.CrossRefPubMed
37.
Lee NH, Choi MJ, Yu H, Kim JI, Cheon HG. Adapalene induces adipose browning through the RARβ-p38 MAPK-ATF2 pathway. Arch Pharmacal Res. 2022;45(5):340–51.CrossRef
38.
Zhang Z, Chen WQ, Zhang SQ, Bai JX, Liu B, Yung KK, Ko JK. Isoliquiritigenin inhibits pancreatic cancer progression through blockade of p38 MAPK-regulated autophagy. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2022;106: 154406.CrossRefPubMed
Metadata
Title
2-phenylacetamide Separated from the seed of Lepidium apetalum Willd. inhibited renal fibrosis via MAPK pathway mediated RAAS and oxidative stress in SHR Rats
Authors
Pei-pei Yuan
Meng Li
Qi Zhang
Meng-nan Zeng
Ying-ying Ke
Ya-xin Wei
Yang Fu
Xiao-ke Zheng
Wei-sheng Feng
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2023
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-023-04012-w

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