Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content

Advertisement

Springer Nature Link
Log in

Epigenome and transcriptome study of moringa isothiocyanate in mouse kidney mesangial cells induced by high glucose, a potential model for diabetic-induced nephropathy

  • Research Article
  • Theme: Natural Products Drug Discovery in Cancer Prevention
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Moringa isothiocyanate (MIC-1) is a bioactive constituent found abundantly in Moringa oleifera which possesses antioxidant and anti-inflammation properties. However, epigenome and transcriptome effects of MIC-1 in kidney mesangial cells challenged with high glucose (HG), a pre-condition for diabetic nephropathy (DN) remain unknown. Herein, we examined the transcriptome gene expression and epigenome DNA methylation in mouse kidney mesangial cells (MES13) using next-generation sequencing (NGS) technology. After HG treatment, epigenome and transcriptome were significantly altered. More importantly, MIC-1 exposure reversed some of the changes caused by HG. Integrative analysis of RNA-Seq data identified 20 canonical pathways showing inverse correlations between HG and MIC-1. These pathways included GNRH signaling, P2Y purigenic receptor signaling pathway, calcium signaling, LPS/IL-1-mediated inhibition of RXR function, and oxidative ethanol degradation III. In terms of alteration of DNA methylation patterns, 173 differentially methylation regions (DMRs) between the HG group and low glucose (LG) group and 149 DMRs between the MIC-1 group and the HG group were found. Several HG related DMRs could be reversed by MIC-1 treatment. Integrative analysis of RNA-Seq and Methyl-Seq data yielded a subset of genes associated with HG and MIC-1, and the gene expression changes may be driven by promoter CpG status. These genes include Col4a2, Tceal3, Ret, and Agt. In summary, our study provides novel insights related to transcriptomic and epigenomic/CpG methylomic alterations in MES13 upon challenged by HG but importantly, MIC-1 treatment reverses some of the transcriptome and epigenome/CpG methylome. These results may provide potential molecular targets and therapeutic strategies for DN.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Abbreviations

DEGs:

Differential expressed genes

DMRs:

Differentially methylation regions

DN:

Diabetic nephropathy

DSS:

Dextran sulfate sodium

ESRD:

End-stage renal disease

HG:

High glucose

IPA:

Ingenuity Pathway Analysis

ROS:

Reactive oxygen species

TSS:

Transcription start site

LG:

Low glucose

MIC-1:

Moringa isothiocyanate

MES13:

Mesangial cells

NGS:

Next-generation sequencing

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

References

  1. Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol. 2016;12(2):73–81.

    CAS  PubMed  Google Scholar 

  2. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, De Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis. 2014;64(4):510–33.

    PubMed  Google Scholar 

  3. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. Jama. 2011;305(24):2532–9.

    PubMed  PubMed Central  Google Scholar 

  4. Shahbazian H, Rezaii I. Diabetic kidney disease; review of the current knowledge. J Renal Injury Prevent. 2013;2(2):73–80.

    Google Scholar 

  5. Yaribeygi H, Atkin SL. Interleukin-18 and diabetic nephropathy: a review. 2019;234(5):5674–82.

  6. Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediators of Inflammation 2012;2012:146154.

    Google Scholar 

  7. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–35.

    CAS  PubMed  Google Scholar 

  8. Kashihara N, Haruna Y, Kondeti KV, Kanwar SY. Oxidative stress in diabetic nephropathy. Curr Med Chem. 2010;17(34):4256–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kato M, Natarajan R. Diabetic nephropathy—emerging epigenetic mechanisms. Nat Rev Nephrol. 2014;10(9):517–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lu Z, Liu N, Wang F. Epigenetic regulations in diabetic nephropathy. J Diabetes Res. 2017;2017:7805058.

    PubMed  PubMed Central  Google Scholar 

  11. Huang D, Cui L, Ahmed S, Zainab F, Wu Q, Wang X, et al. An overview of epigenetic agents and natural nutrition products targeting DNA methyltransferase, histone deacetylases and microRNAs. Food Chem Toxicol. 2019;123:574–94.

    CAS  PubMed  Google Scholar 

  12. Guo Y, Su Z-Y, Kong A-NT. Current perspectives on epigenetic modifications by dietary chemopreventive and herbal phytochemicals. Curr Pharmacol Rep. 2015;1(4):245–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Yuqing Yang A, Kim H, Li W, Tony Kong A-N. Natural compound-derived epigenetic regulators targeting epigenetic readers, writers and erasers. Curr Top Med Chem. 2016;16(7):697–713.

    Google Scholar 

  14. Bennett RN, Mellon FA, Foidl N, Pratt JH, Dupont MS, Perkins L, et al. Profiling glucosinolates and phenolics in vegetative and reproductive tissues of the multi-purpose trees Moringa oleifera L. (Horseradish tree) and Moringa stenopetala L. J Agric Food Chem. 2003;51(12):3546–53.

    CAS  PubMed  Google Scholar 

  15. Leone A, Spada A, Battezzati A, Schiraldi A, Aristil J, Bertoli S. Cultivation, genetic, ethnopharmacology, phytochemistry and pharmacology of Moringa oleifera leaves: an overview. Int J Mol Sci. 2015;16(6):12791–835.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Yassa HD, Tohamy AF. Extract of Moringa oleifera leaves ameliorates streptozotocin-induced diabetes mellitus in adult rats. Acta Histochem. 2014;116(5):844–54.

    PubMed  Google Scholar 

  17. Cheng D, Gao L, Su S, Sargsyan D, Wu R, Raskin I, et al. Moringa isothiocyanate activates Nrf2: potential role in diabetic nephropathy. AAPS J. 2019;21(2):31.

    PubMed  Google Scholar 

  18. Wang C, Wu R, Sargsyan D, Zheng M, Li S, Yin R, et al. CpG methyl-seq and RNA-seq epigenomic and transcriptomic studies on the preventive effects of Moringa isothiocyanate in mouse epidermal JB6 cells induced by the tumor promoter TPA. J Nutr Biochem. 2019;68:69–78.

    CAS  PubMed  Google Scholar 

  19. Kim D, Li HY, Lee JH, Oh YS, Jun H-S. Lysophosphatidic acid increases mesangial cell proliferation in models of diabetic nephropathy via Rac1/MAPK/KLF5 signaling. Exp Mol Med. 2019;51(2):18.

    PubMed  PubMed Central  Google Scholar 

  20. Yano N, Suzuki D, Endoh M, Zhao TC, Padbury JF, Tseng Y-T. A novel phosphoinositide 3-kinase-dependent pathway for angiotensin II/AT-1 receptor-mediated induction of collagen synthesis in MES-13 mesangial cells. J Biol Chem. 2007;282(26):18819–30.

    CAS  PubMed  Google Scholar 

  21. Yano N, Suzuki D, Endoh M, Cao TN, Dahdah JR, Tseng A, et al. High ambient glucose induces angiotensin-independent AT-1 receptor activation, leading to increases in proliferation and extracellular matrix accumulation in MES-13 mesangial cells. Biochem J. 2009;423(1):129–43.

    CAS  PubMed  Google Scholar 

  22. Ho C, Lee PH, Hsu YC, Wang FS, Huang YT, Lin CL. Sustained Wnt/beta-catenin signaling rescues high glucose induction of transforming growth factor-beta1-mediated renal fibrosis. Am J Med Sci. 2012;344(5):374–82.

    PubMed  Google Scholar 

  23. Catherwood MA, Powell LA, Anderson P, McMaster D, Sharpe PC, Trimble ER. Glucose-induced oxidative stress in mesangial cells. Kidney Int. 2002;61(2):599–608.

    CAS  PubMed  Google Scholar 

  24. Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol. 2008;26(10):1135–45.

    CAS  PubMed  Google Scholar 

  25. Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet. 2016;17(6):333–51.

    CAS  Google Scholar 

  26. Zhang Z, Yuan W, Sun L, Szeto F, Wong K, Li X, et al. 1,25-Dihydroxyvitamin D3 targeting of NF-κB suppresses high glucose-induced MCP-1 expression in mesangial cells. Kidney Int. 2007;72(2):193–201.

    CAS  PubMed  Google Scholar 

  27. Li W, Sargsyan D, Wu R, Li S, Wang L, Cheng D, et al. DNA methylome and transcriptome alterations in high glucose-induced diabetic nephropathy cellular model and identification of novel targets for treatment by tanshinone IIA. Chem Res Toxicol. 2019;32:1977–88.

    CAS  PubMed  Google Scholar 

  28. Yang Y, Wu R, Sargsyan D, Yin R, Kuo H-C, Yang I, et al. UVB drives different stages of epigenome alterations during progression of skin cancer. Cancer Lett. 2019;449:20–30.

    CAS  PubMed  Google Scholar 

  29. Guo Y, Wu R, Gaspar JM, Sargsyan D, Su Z-Y, Zhang C, et al. DNA methylome and transcriptome alterations and cancer prevention by curcumin in colitis-accelerated colon cancer in mice. Carcinogenesis. 2018;39(5):669–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Storey JD. The positive false discovery rate: a Bayesian interpretation and the q-value. Ann Stat. 2003;31(6):2013–35.

    Google Scholar 

  31. Gaspar JM, Hart RP. DMRfinder: efficiently identifying differentially methylated regions from MethylC-seq data. BMC Bioinf. 2017;18(1):528.

    Google Scholar 

  32. Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc Ther. 2012;30(1):49–59.

    CAS  PubMed  Google Scholar 

  33. Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013;83(6):1029–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ha H, Lee HB. Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucose. Kidney Int. 2000;58:S19–25.

    Google Scholar 

  35. Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD (P) H oxidase in cultured vascular cells. Diabetes. 2000;49(11):1939–45.

    CAS  PubMed  Google Scholar 

  36. Kim Y, Wu AG, Jaja-Chimedza A, Graf BL, Waterman C, Verzi MP, et al. Isothiocyanate-enriched moringa seed extract alleviates ulcerative colitis symptoms in mice. PLoS One. 2017;12(9):e0184709.

    PubMed  PubMed Central  Google Scholar 

  37. Uruno A, Motohashi H. The Keap1–Nrf2 system as an in vivo sensor for electrophiles. Nitric Oxide. 2011;25(2):153–60.

    CAS  PubMed  Google Scholar 

  38. Ahmed SMU, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta (BBA)-Mol Basisf Dis. 2017;1863(2):585–97.

    CAS  Google Scholar 

  39. Itoh K, Mochizuki M, Ishii Y, Ishii T, Shibata T, Kawamoto Y, et al. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Δ12, 14-prostaglandin J2. Mol Cell Biol. 2004;24(1):36–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59.

    CAS  PubMed  Google Scholar 

  41. Oba S, Ayuzawa N, Nishimoto M, Kawarazaki W, Ueda K, Hirohama D, et al. Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells. Sci Rep. 2018;8(1):16338.

    PubMed  PubMed Central  Google Scholar 

  42. Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484–92.

    CAS  PubMed  Google Scholar 

  43. Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell. 2014;26(4):577–90.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by R01AT009152 from the National Center for Complementary & Alternative Medicine (NCCAM) and R01CA200129 from the National Cancer Institute (NCI). The authors appreciate all the members of Dr. Kong’s laboratory for their invaluable support and technical assistance.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA

    Shanyi Li, Wenji Li, Renyi Wu, Ran Yin, Davit Sargsyan & Ah-Ng Kong

  2. Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People’s Republic of China

    Wenji Li

  3. Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, People’s Republic of China

    Wenji Li

  4. Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA

    Davit Sargsyan

  5. Department of Plant Biology & Pathology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, 08901, USA

    Ilya Raskin

Authors
  1. Shanyi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenji Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Renyi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ran Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Davit Sargsyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ilya Raskin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ah-Ng Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ah-Ng Kong.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Guest Editors: Ah-Ng Tony Kong and Chi Chen

Publisher’s Note

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

Electronic supplementary material

ESM 1

(XLSX 21 kb)

ESM 2

(XLSX 42 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Li, W., Wu, R. et al. Epigenome and transcriptome study of moringa isothiocyanate in mouse kidney mesangial cells induced by high glucose, a potential model for diabetic-induced nephropathy. AAPS J 22, 8 (2020). https://doi.org/10.1208/s12248-019-0393-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-019-0393-z

KEY WORDS

Search

Navigation