Skip to main content
SpringerLink
Log in

Novel biphenyl diester derivative AB-38b inhibits NLRP3 inflammasome through Nrf2 activation in diabetic nephropathy

  • Original Article
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

A Correction to this article was published on 16 February 2022

A Correction to this article was published on 22 January 2020

This article has been updated

Abstract

Inflammation reaction mediated by NLRP3 inflammasome and Nrf2-related oxidative stress are vital participants in the development of diabetic nephropathy (DN) and closely associated to kidney fibrosis. Nrf2, a known antioxidative transcription factor, has been reported to activate NLRP3 inflammasome through its downstream factors (HO-1, NQO1, etc.) recently. AB38b is a newly synthesized biphenyl diester derivative with a Nrf2 activation property. This research aims to evaluate the renal protective effects of AB-38b and to elucidate the anti-inflammation mechanisms involved. Type 2 diabetic mice induced by high fat diet with streptozocin (STZ) and high glucose-cultured mouse glomerular mesangial cells (GMCs) were used in current study. Results showed that administration of AB-38b improved the kidney function while attenuated renal fibrosis progression in diabetic mice together with reducing the extracellular matrix (ECM) accumulation of GMCs cultured in high glucose. Mechanistically, treatment with AB-38b significantly decreased the high level of NLRP3 inflammasome in diabetic condition by inhibiting the ROS/TXNIP/NLRP3 signaling pathway. And meanwhile, AB-38b treatment effectively improved Nrf2 signaling during diabetic condition. Furthermore, knocking down the gene expression of Nrf2 by siRNA in GMCs abolished the inhibition effect of AB-38b on NLRP3 inflammasome activation and ECM accumulation. Taken together, our data suggest that AB-38b was able to improve the renal function of diabetic mice, and the NLRP3 inflammasome inhibition effect of AB-38b was responsible for the renal protective effect. Further exploration indicate that Nrf2 plays pivotal role in AB-38b’s attenuation of DN progression through inhibiting NLRP3 inflammasome activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Change history

References

  • Abdel-Hameid NA. Protective role of dimethyl diphenyl bicarboxylate (DDB) against erythromycin induced hepatotoxicity in male rats. Toxicol in Vitro. 2007;21(4):618–25.

    Article  CAS  Google Scholar 

  • Ahmadi S, Ebrahimi SS, Oryan S. Blockades of ATP-sensitive potassium channels and L-type calcium channels improve analgesic effect of morphine in alloxan-induced diabetic mice. Pathophysiology. 2012;19:171–7. https://doi.org/10.1016/j.pathophys.2012.04.007.

    Article  CAS  PubMed  Google Scholar 

  • Bai RX, Xu YY, Qin G, Chen YM, Wang HF, Wang M, et al. Repression of TXNIP-NLRP3 axis restores intestinal barrier function via inhibition of myeloperoxidase activity and oxidative stress in nonalcoholic steatohepatitis. J Cell Physiol. 2019;234(5):7524–38.

    Article  CAS  Google Scholar 

  • Chen J, Liu W, Yi H, Hu X, Peng L, Yang F. The natural rotenoid deguelin ameliorates diabetic neuropathy by decreasing oxidative stress and plasma glucose levels in rats via the Nrf2 signalling pathway. Cell Physiol Biochem. 2018;48(3):1164–76.

    Article  CAS  Google Scholar 

  • Chen YJ, Kong L, Tang ZZ, Zhang YM, Liu Y, Wang TY, et al. Hesperetin ameliorates diabetic nephropathy in rats by activating Nrf2/ARE/glyoxalase 1 pathway. Biomed Pharmacother. 2019a;111:1166–75.

    Article  CAS  Google Scholar 

  • Chen YJ, Tang ZZ, Du L, Liu Y, Lu Q, Ma TF, et al. A novel compound AB-38b improves diabetes-associated cognitive decline in mice via activation of Nrf2/ARE pathway. Brain Res Bull. 2019b Aug;150:160–7. https://doi.org/10.1016/j.brainresbull.2019.05.010.

    Article  CAS  PubMed  Google Scholar 

  • Fan X, Jiang Y, Wang Y, Tan H, Zeng H, Wang Y, et al. Wuzhi tablet (Schisandra Sphenanthera extract) protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of NRF2-ARE and p53/p21 pathways. Drug Metab Dispos. 2014;42(12):1982–90.

    Article  Google Scholar 

  • Fu Y, Wu N, Zhao D. Function of NLRP3 in the pathogenesis and development of diabetic nephropathy. Med Sci Monit. 2017;23:3878–84.

    Article  Google Scholar 

  • Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058–70.

    Article  CAS  Google Scholar 

  • Guo M, Liu D, Sha Q, et al. Succinic acid enhanced quantitative determination of blood modified nucleosides in the development of diabetic nephropathy based on hydrophilic interaction liquid chromatography mass spectrometry. J Pharm Biomed Anal 2019;164:309–316. https://doi.org/10.1016/j.jpba.2018.10.042.

  • Han Y, Xu X, Tang C, Gao P, Chen X, Xiong X, et al. Reactive oxygen species promote tubular injury in diabetic nephropathy: the role of the mitochondrial ros-txnip-nlrp3 biological axis. Redox Biol. 2018;16:32–46. https://doi.org/10.1016/j.redox.2018.02.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu C, Sun L, Xiao L, Han Y, Fu X, Xiong X, et al. Insights into the mechanisms involved in the expression and regulation of extracellular matrix proteins in diabetic nephropathy. Curr Med Chem. 2015;22(24):2858–70.

    Article  CAS  Google Scholar 

  • Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116.

    Article  CAS  Google Scholar 

  • Kim SJ, Lee SM. NLRP3 inflammasome activation in D-galactosamine and lipopolysaccharide-induced acute liver failure: role of heme oxygenase-1. Free Radic Biol Med. 2013;65:997–1004.

    Article  CAS  Google Scholar 

  • Kolset SO, Reinholt FP, Jenssen T. Diabetic nephropathy and extracellular matrix. J Histochem Cytochem. 2012;60(12):976–86.

    Article  CAS  Google Scholar 

  • Lei L, Li CC, Qian X, et al. Quercetin inhibited mesangial cell proliferation of early diabetic nephropathy through the Hippo pathway. Pharmacol Res. 2019;146:104320.https://doi.org/10.1016/j.phrs.2019.104320

  • Li LH, Lin JS, Chiu HW, Lin WY, Ju TC, Chen FH, et al. Mechanistic insight into the activation of the nlrp3 inflammasome by in macrophages. Front Immunol. 2019;10:1815. https://doi.org/10.3389/fimmu.2019.01815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011;7(12):684–96.

    Article  CAS  Google Scholar 

  • Liu YW, Hao YC, Chen YJ, et al. Protective effects of sarsasapogenin against early stage of diabetic nephropathy in rats. Phytother Res 2018;32:1574–1582. https://doi.org/10.1002/ptr.6088.

  • Liu YW, Liu XL, Kong L, Zhang MY, Chen YJ, Zhu X, et al. Neuroprotection of quercetin on central neurons against chronic high glucose through enhancement of Nrf2/ARE/glyoxalase-1 pathway mediated by phosphorylation regulation. Biomed Pharmacother. 2019a;109:2145–54.

    Article  CAS  Google Scholar 

  • Liu J, Li S, Sun D. Calcium dobesilate and micro-vascular diseases. Life Sci. 2019b;221:348–53.

    Article  CAS  Google Scholar 

  • London NR, Tharakan A, Mendiola M, et al. Nrf2 activation via Keap1 deletion or sulforaphane treatment reduces Ova-induced sinonasal inflammation. Allergy. 2019. https://doi.org/10.1111/all.13766.

  • Luo B, Huang F, Liu Y, et al. NLRP3 Inflammasome as a Molecular Marker in Diabetic Cardiomyopathy. Front Physiol 2017;8:519. https://doi.org/10.3389/fphys.2017.00519.

  • Lv J, Su W, Yu Q, Zhang M, Di C, Lin X, et al. Heme oxygenase-1 protects airway epithelium against apoptosis by targeting the proinflammatory NLRP3-RXR axis in asthma. J Biol Chem. 2018;293(48):18454–65.

    Article  CAS  Google Scholar 

  • Martinon F. Signaling by ROS drives inflammasome activation. Eur J Immunol. 2010;40(3):616–9.

    Article  CAS  Google Scholar 

  • Mishra R, Emancipator SN, Kern T, Simonson MS. High glucose evokes an intrinsic proapoptotic signaling pathway in mesangial cells. Kidney Int. 2005;67(1):82–93.

    Article  CAS  Google Scholar 

  • Olofsson EM, Marklund SL, Karlsson K, Brannstrom T, Behndig A. In vitro glucose-induced cataract in copper-zinc superoxide dismutase null mice. Exp Eye Res. 2005;81(6):639–46.

    Article  CAS  Google Scholar 

  • Onochie OE, Onyejose AJ, Rich CB, Trinkaus-Randall V. The role of hypoxia in corneal extracellular matrix deposition and cell motility. Anat Rec (Hoboken). 2019.

  • Ozmen B, Ozmen D, Erkin E, Guner I, Habif S, Bayindir O. Lens superoxide dismutase and catalase activities in diabetic cataract. Clin Biochem. 2002;35(1):69–72.

    Article  CAS  Google Scholar 

  • Prochnicki T, Mangan MS, Latz E. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Res. 2016;5.

  • Qiao Y, Tian X, Men L, Li S, Chen Y, Xue M, et al. Spleen tyrosine kinase promotes NLR family pyrin domain containing 3 inflammasomemediated IL1beta secretion via cJun Nterminal kinase activation and cell apoptosis during diabetic nephropathy. Mol Med Rep. 2018;18(2):1995–2008.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu YY, Tang LQ. Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy. Pharmacol Res. 2016;114:251–64.

    Article  CAS  Google Scholar 

  • Samra YA, Said HS, Elsherbiny NM, Liou GI, El-Shishtawy MM, Eissa LA. Cepharanthine and piperine ameliorate diabetic nephropathy in rats: role of NF-kappaB and NLRP3 inflammasome. Life Sci. 2016;157:187–99.

    Article  CAS  Google Scholar 

  • Schmidt A, von Woedtke T, Vollmar B, Hasse S, Bekeschus S. Nrf2 signaling and inflammation are key events in physical plasma-spurred wound healing. Theranostics. 2019;9(4):1066–84.

    Article  CAS  Google Scholar 

  • Silva-Islas CA. Canonical and non-canonical mechanisms of Nrf2 activation. Pharmacol Res. 2018;134:92–9. https://doi.org/10.1016/j.phrs.2018.06.013.

    Article  CAS  PubMed  Google Scholar 

  • Simonson MS. Phenotypic transitions and fibrosis in diabetic nephropathy. Kidney Int. 2007;71(9):846–54.

    Article  CAS  Google Scholar 

  • Sun H, Liu GT. Chemopreventive effect of dimethyl dicarboxylate biphenyl on malignant transformation of WB-F344 rat liver epithelial cells. Acta Pharmacol Sin. 2005;26(11):1339–44.

    Article  CAS  Google Scholar 

  • Tonnies T, Stahl-Pehe A, Baechle C, Castillo K, Yossa R, Holl RW, et al. Diabetic nephropathy and quality of life among youths with long-duration type 1 diabetes: A population-based cross-sectional study. Pediatr Diabetes. 2019.

  • Tziomalos K, Athyros VG. Diabetic nephropathy: new risk factors and improvements in diagnosis. Rev Diabet Stud. 2015;12(1-2):110–8.

    Article  Google Scholar 

  • Wang J, Fang H, Dong B, et al. Effects of Free Anthraquinones Extract from the Rhubarb on Cell Proliferation and Accumulation of Extracellular Matrix in High Glucose Cultured-Mesangial Cells. Korean J Physiol Pharmacol 2015;19:485–489. https://doi.org/10.4196/kjpp.2015.19.6.485.

  • Wang J, Fang H, Dong B, Wang D, Li Y, Chen X, et al. Effects of Free Anthraquinones extract from the rhubarb on cell proliferation and accumulation of extracellular matrix in high glucose cultured-mesangial cells. Korean J Physiol Pharmacol. 2015a;19(6):485–9.

    Article  CAS  Google Scholar 

  • Wang JY, Liu S, Qin N, Yang QQ, Guo H, Zhang F, et al. Jak2/Stat1 pathway mediated tetrahydrobiopterin up-regulation contributes to nitric oxide overproduction in high-glucose cultured rat mesangial cells. Can J Physiol Pharmacol. 2015b;93(1):81–9.

    Article  CAS  Google Scholar 

  • Wang K, Lv Q, Miao YM, Qiao SM, Dai Y, Wei ZF. Cardamonin, a natural flavone, alleviates inflammatory bowel disease by the inhibition of NLRP3 inflammasome activation via an AhR/Nrf2/NQO1 pathway. Biochem Pharmacol. 2018;155:494–509.

    Article  CAS  Google Scholar 

  • Wu Y, Ge G. Complexity of type IV collagens: from network assembly to function. Biol Chem. 2019;400(5):565–74.

    Article  CAS  Google Scholar 

  • Xu X, Zhang L, Ye X, Hao Q, Zhang T, Cui G, et al. Nrf2/ARE pathway inhibits ROS-induced NLRP3 inflammasome activation in BV2 cells after cerebral ischemia reperfusion. Inflamm Res. 2018;67(1):57–65.

    Article  CAS  Google Scholar 

  • Yao H, Zhang W, Wu H, et al. Sikokianin A from protects PC12 cells against OGD/R-induced injury via inhibiting oxidative stress and activating Nrf2. Nat Prod Res 2019;33:3450–3453. https://doi.org/10.1080/14786419.2018.1480019.

  • Yaribeygi H, Atkin SL, Simental-Mendia LE, Barreto GE, Sahebkar A. Anti-inflammatory effects of resolvins in diabetic nephropathy: mechanistic pathways. J Cell Physiol. 2019a.

  • Yaribeygi H, Katsiki N, Butler AE, Sahebkar A. Effects of antidiabetic drugs on NLRP3 inflammasome activity, with a focus on diabetic kidneys. Drug Discov Today. 2019b;24(1):256–62.

    Article  CAS  Google Scholar 

  • Ying Q, Wu G. Molecular mechanisms involved in podocyte EMT and concomitant diabetic kidney diseases: an update. Ren Fail. 2017;39(1):474–83.

    Article  Google Scholar 

  • Yu X, Lan P, Hou X, Han Q, Lu N, Li T, et al. HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1beta production via suppressing the NF-kappaB pathway and ROS production. J Hepatol. 2017;66(4):693–702.

    Article  CAS  Google Scholar 

  • Zeng W, Qi W, Mu J, Wei Y, Yang LL, Zhang Q, et al. MG132 protects against renal dysfunction by regulating Akt-mediated inflammation in diabetic nephropathy. Sci Rep. 2019;9(1):2049.

    Article  Google Scholar 

  • Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11(2):136–40.

    Article  CAS  Google Scholar 

  • Zhu X, Cheng YQ, Du L, Li Y, Zhang F, Guo H, et al. Mangiferin attenuates renal fibrosis through down-regulation of osteopontin in diabetic rats. Phytother Res. 2015;29(2):295–302.

    Article  CAS  Google Scholar 

Download references

Funding

The work was financially supported by the National Natural Science Foundation of China (No. 81473257), the Qing Lan project, the Natural Science Foundation of Jiangsu Province (No. BK20151155), the “333” Foundation of Jiangsu Province (No. BRA2015329), the Key Natural Science Foundation of Jiangsu Higher Education Institutions of China (No. 15KJA310005), and The Science and Technology project of Xuzhou (No. KC18202).

Author information

Author notes

  1. Lei Du, Jin Wang and Yibing Chen contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China

    Lei Du, Jin Wang, Yibing Chen, Xizhi Li, Lei Wang, Yuan Li, Xiaoping Jin, Xiaoke Gu, Meng Hao, Xia Zhu, Xiaoxing Yin & Qian Lu

Authors
  1. Lei Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yibing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xizhi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaoping Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoke Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Meng Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xia Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiaoxing Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qian Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiaoxing Yin or Qian Lu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 135 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, L., Wang, J., Chen, Y. et al. Novel biphenyl diester derivative AB-38b inhibits NLRP3 inflammasome through Nrf2 activation in diabetic nephropathy. Cell Biol Toxicol 36, 243–260 (2020). https://doi.org/10.1007/s10565-019-09501-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-019-09501-8

Keywords

Search

Navigation