Arctigenin Attenuates Diabetic Kidney Disease Through the Activation of PP2A in Podocytes

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Oct 6

PMID 31586053

Citations 63

Authors

Yifei Zhong

Kyung Lee

Yueyi Deng

Yueming Ma

Yiping Chen

Xueling Li

Chengguo Wei

Shumin Yang

Tianming Wang

Nicholas J Wong

Alecia N Muwonge

Evren U Azeloglu

Weijia Zhang

Bhaskar Das

John Cijiang He

Ruijie Liu

Affiliations

Soon will be listed here.

Abstract

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients. However, whether ATG specifically provides renoprotection in DKD is not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2 A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.

Citing Articles

Global trends and prospects related to macrophage in chronic kidney disease: a bibliometric analysis.

Hu Y, Wang Y, Hong H, Chen Y, Zhou Q, Zhu G Ren Fail. 2024; 46(2):2423846.

PMID: 39572163 PMC: 11583328. DOI: 10.1080/0886022X.2024.2423846.

Fructus Arctii Mitigates Depressive Disorder via the Let-7e-Modulated Toll-Like Receptor (TLR) Signaling Pathway.

Zhang W, Zhou Q Brain Behav. 2024; 14(11):e70132.

PMID: 39538967 PMC: 11560858. DOI: 10.1002/brb3.70132.

β-Sitosterol Mitigates Apoptosis, Oxidative Stress and Inflammatory Response by Inactivating TLR4/NF-кB Pathway in Cell Models of Diabetic Nephropathy.

Yang S, Zhang Y, Zheng C Cell Biochem Biophys. 2024; 83(1):1249-1262.

PMID: 39424766 DOI: 10.1007/s12013-024-01559-4.

Mechanisms of hepatic and renal injury in lipid metabolism disorders in metabolic syndrome.

Rong J, Zhang Z, Peng X, Li P, Zhao T, Zhong Y Int J Biol Sci. 2024; 20(12):4783-4798.

PMID: 39309427 PMC: 11414397. DOI: 10.7150/ijbs.100394.

Predicting prospective therapeutic targets of Bombyx batryticatus for managing diabetic kidney disease through network pharmacology analysis.

Chang J, Wang J, Li X, Zhong Y Medicine (Baltimore). 2024; 103(37):e39598.

PMID: 39287308 PMC: 11404872. DOI: 10.1097/MD.0000000000039598.

References

Hsieh C, Hsiao G, Hsu M, Wang Y, Sheu J . PMC, a potent hydrophilic α-tocopherol derivative, inhibits NF-κB activation via PP2A but not IκBα-dependent signals in vascular smooth muscle cells. J Cell Mol Med. 2014; 18(7):1278-89. PMC: 4124013. DOI: 10.1111/jcmm.12277. View

Sun Y, Zang Z, Zhong L, Wu M, Su Q, Gao X . Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay. PLoS One. 2013; 8(5):e63354. PMC: 3653934. DOI: 10.1371/journal.pone.0063354. View

Yang J, Fan G, Wadzinski B, Sakurai H, Richmond A . Protein phosphatase 2A interacts with and directly dephosphorylates RelA. J Biol Chem. 2001; 276(51):47828-33. PMC: 2665282. DOI: 10.1074/jbc.M106103200. View

Zhang W, Jiang Z, He B, Liu X . Arctigenin Protects against Lipopolysaccharide-Induced Pulmonary Oxidative Stress and Inflammation in a Mouse Model via Suppression of MAPK, HO-1, and iNOS Signaling. Inflammation. 2015; 38(4):1406-14. PMC: 7102291. DOI: 10.1007/s10753-015-0115-3. View

Crispin J, Apostolidis S, Rosetti F, Keszei M, Wang N, Terhorst C . Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism. J Immunol. 2012; 188(8):3567-71. PMC: 3324672. DOI: 10.4049/jimmunol.1200143. View

Liu Y, Wang G, Yang M, Chen H, Zhao Y, Yang S . Arctigenin reduces blood pressure by modulation of nitric oxide synthase and NADPH oxidase expression in spontaneously hypertensive rats. Biochem Biophys Res Commun. 2015; 468(4):837-42. DOI: 10.1016/j.bbrc.2015.11.041. View

Zhong Y, Menon M, Deng Y, Chen Y, He J . Recent Advances in Traditional Chinese Medicine for Kidney Disease. Am J Kidney Dis. 2015; 66(3):513-22. DOI: 10.1053/j.ajkd.2015.04.013. View

Li W, Chen Z, Zong Y, Gong F, Zhu Y, Zhu Y . PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of IKKα and sustained activation of the NF-κB pathway. Cancer Lett. 2011; 304(2):117-27. DOI: 10.1016/j.canlet.2011.02.009. View

Chen G, Li H, Dou D, Xu Y, Jiang H, Li F . (-)-Arctigenin as a lead compound for anticancer agent. Nat Prod Res. 2013; 27(23):2251-5. DOI: 10.1080/14786419.2013.821120. View

10.

Du Y, Kowluru A, Kern T . PP2A contributes to endothelial death in high glucose: inhibition by benfotiamine. Am J Physiol Regul Integr Comp Physiol. 2010; 299(6):R1610-7. PMC: 3774204. DOI: 10.1152/ajpregu.00676.2009. View

11.

Butkevich E, Bodensiek K, Fakhri N, von Roden K, Schaap I, Majoul I . Drebrin-like protein DBN-1 is a sarcomere component that stabilizes actin filaments during muscle contraction. Nat Commun. 2015; 6:7523. DOI: 10.1038/ncomms8523. View

12.

Sontag J, Nunbhakdi-Craig V, White 3rd C, Halpain S, Sontag E . The protein phosphatase PP2A/Bα binds to the microtubule-associated proteins Tau and MAP2 at a motif also recognized by the kinase Fyn: implications for tauopathies. J Biol Chem. 2012; 287(18):14984-93. PMC: 3340226. DOI: 10.1074/jbc.M111.338681. View

13.

Azeloglu E, Hardy S, Eungdamrong N, Chen Y, Jayaraman G, Chuang P . Interconnected network motifs control podocyte morphology and kidney function. Sci Signal. 2014; 7(311):ra12. PMC: 4220789. DOI: 10.1126/scisignal.2004621. View

14.

Sun G, Li C, Cui W, Guo Q, Dong C, Zou H . Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy. J Diabetes Res. 2015; 2016:5749857. PMC: 4662991. DOI: 10.1155/2016/5749857. View

15.

Kar S, Palit S, Ball W, Das P . Carnosic acid modulates Akt/IKK/NF-κB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells. Apoptosis. 2012; 17(7):735-47. DOI: 10.1007/s10495-012-0715-4. View

16.

Weil E, Lemley K, Mason C, Yee B, Jones L, Blouch K . Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int. 2012; 82(9):1010-7. PMC: 3472108. DOI: 10.1038/ki.2012.234. View

17.

Schmid H, Boucherot A, Yasuda Y, Henger A, Brunner B, Eichinger F . Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy. Diabetes. 2006; 55(11):2993-3003. DOI: 10.2337/db06-0477. View

18.

Ong S, Schenone M, Margolin A, Li X, Do K, Doud M . Identifying the proteins to which small-molecule probes and drugs bind in cells. Proc Natl Acad Sci U S A. 2009; 106(12):4617-22. PMC: 2649954. DOI: 10.1073/pnas.0900191106. View

19.

Wang H, Chen Y . [Clinical observation on treatment of diabetic nephropathy with compound fructus arctii mixture]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004; 24(7):589-92. View

20.

Peitsch W, Grund C, Kuhn C, Schnolzer M, SPRING H, Schmelz M . Drebrin is a widespread actin-associating protein enriched at junctional plaques, defining a specific microfilament anchorage system in polar epithelial cells. Eur J Cell Biol. 1999; 78(11):767-78. DOI: 10.1016/S0171-9335(99)80027-2. View