Journal of Nutrition and Health

The Korean Nutrition Society (한국영양학회)
권호 표지
DOI QR코드

DOI QR Code

Dietary nobiletin suppresses TGF-β1- Src-caveolin-1 dependent signaling involved with high glucose-induced renal mesangial matrix accumulation

고혈당으로 유도된 신장 mesangial cell 에서 nobiletin의 matrix accumulation 과 TGF-β1-Src-caveolin-1 signaling에 의한 사구체 경화증 억제효과

  • Received : 2019.12.01
  • Accepted : 2020.01.08
  • Published : 2020.02.29
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: Diabetic nephropathy is one of the most important diabetic complications prompted by chronic hyperglycemia, characterized by glomerulosclerosis, tubular fibrosis, and it eventually causes kidney failure. Nobiletin is a polymethoxyflavone present in tangerine and other citrus peels, and has anti-cancer and anti-inflammatory effects. This study investigated the effects of nobiletin on glomerular fibrosis through inhibition of the transforming growth factor (TGF)-β1-Src-caveolin-1 pathway. Methods: Human renal mesangial cells (HRMC) were incubated in media containing 33 mM glucose with or without 1-20 uM nobiletin for 3 day. The cellular expression levels of fibrogenic collagen IV, fibronectin, connective tissue growth factor (CTGF), TGF-β1, Src and caveolin-1 were all examined. In addition, TGF-β1, Src and caveolin-1 proteins were screened to reveal the relationship among TGF-β1-Src-caveolin-1 signaling in glomerular fibrosis. Results: High glucose promoted the production of collagen IV, fibronectin and CTGF in HRMC, which was inhibited in a dose dependent manner by 1-20 uM nobiletin. The Western blot data showed that high glucose elevated the expression of TGF-β1, Src, caveolin-1 and Rho GTPase. When nobiletin was treated to the HRMC exposed to high glucose, the expression of TGF-β1-Src-caveolin-1 was dampened. Finally, TGF-β1-Src-caveolin-1 signaling pathway was activated in high glucose-exposed HRMC, and such activation was encumbered by nobiletin. Conclusion: These result demonstrated that nobiletin blunted high glucose-induced extracellular matrix accumulation via inhibition of the TGF-β1-Src-caveolin-1 related intracellular signaling pathway. Nobiletin may be a potent renoprotective agent to counteract diabetes-associated glomerular fibrosis that leads to kidney failure.

본 연구에서는 고혈당으로 인해 유발되는 당뇨병성 신장병증의 대표적인 증상인 사구체 경화증을 완화시키는 nobiletin의 효능에 대해 알아보고자 하였다. 신장 세포인 HRMC를 이용하여 고혈당에서의 세포외 기질 축적 단백질의 발현과 경화에 관여하는 신호 전달 억제 효능을 확인한 결과 nobiletin은 고혈당의 자극에 의해 증가하는 섬유화 단백질인 collagen IV, fibronectin 그리고 CTGF의 발현을 억제하였으며, 여기에 관여하는 TGF-β1-Src-caveolin-1 신호 전달 경로를 통해 사구체 경화증을 억제하는 것을 확인하였다. 따라서 nobiletin은 고혈당으로 유도된 당뇨병성 신장병증에 있어 사구체 경화증을 예방하는 기능성 성분으로서의 활용 가능성을 확인하였다.

Keywords

References

  1. Ban CR, Twigg SM. Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag 2008; 4(3): 575-596. https://doi.org/10.2147/VHRM.S1991
  2. Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16 Suppl 1: S30-S33. https://doi.org/10.1681/ASN.2004110970
  3. Pozzi A, Voziyan PA, Hudson BG, Zent R. Regulation of matrix synthesis, remodeling and accumulation in glomerulosclerosis. Curr Pharm Des 2009; 15(12): 1318-1333. https://doi.org/10.2174/138161209787846748
  4. Fukuda N, Tahira Y, Matsuda H, Matsumoto K. Transforming growth factor-beta as a treatment target in renal diseases. J Nephrol 2009; 22(6): 708-715.
  5. Li J, Lim SS, Lee JY, Kim JK, Kang SW, Kim JL, et al. Purple corn anthocyanins dampened high-glucose-induced mesangial fibrosis and inflammation: possible renoprotective role in diabetic nephropathy. J Nutr Biochem 2012; 23(4): 320-331. https://doi.org/10.1016/j.jnutbio.2010.12.008
  6. Ungefroren H, Witte D, Lehnert H. The role of small GTPases of the Rho/Rac family in TGF-${\beta}$-induced EMT and cell motility in cancer. Dev Dyn 2018; 247(3): 451-461. https://doi.org/10.1002/dvdy.24505
  7. Li J, Lim SS, Lee ES, Gong JH, Shin D, Kang IJ, et al. Isoangustone A suppresses mesangial fibrosis and inflammation in human renal mesangial cells. Exp Biol Med (Maywood) 2011; 236(4): 435-444. https://doi.org/10.1258/ebm.2010.010325
  8. Peng F, Wu D, Gao B, Ingram AJ, Zhang B, Chorneyko K, et al. RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease. Diabetes 2008; 57(6): 1683-1692. https://doi.org/10.2337/db07-1149
  9. Razani B, Zhang XL, Bitzer M, von Gersdorff G, Bottinger EP, Lisanti MP. Caveolin-1 regulates transforming growth factor (TGF)-${\beta}$/SMAD signaling through an interaction with the TGF-${\beta}$ type I receptor. J Biol Chem 2001; 276(9): 6727-6738. https://doi.org/10.1074/jbc.M008340200
  10. Van Krieken R, Krepinsky JC. Caveolin-1 in the pathogenesis of diabetic nephropathy: potential therapeutic target? Curr Diab Rep 2017; 17(3): 19. https://doi.org/10.1007/s11892-017-0844-9
  11. Lu Y, Tang L, Li Y, He Q. High glucose-induced fibronectin upregulation in cultured mesangial cells involves caveolin-1-dependent RhoA-GTP activation via Src kinase. Mol Med Rep 2016; 14(1): 963-968. https://doi.org/10.3892/mmr.2016.5312
  12. Youn K, Lee S, Jun M. Discovery of nobiletin from citrus peel as a potent inhibitor of ${\beta}$-amyloid peptide toxicity. Nutrients 2019; 11(11): 2648. https://doi.org/10.3390/nu11112648
  13. Huang H, Li L, Shi W, Liu H, Yang J, Yuan X, et al. The multifunctional effects of nobiletin and its metabolites in vivo and in vitro. Evid Based Complement Alternat Med 2016; 2016: 2918796.
  14. Wilson HM, Stewart KN. Glomerular epithelial and mesangial cell culture and characterization. Methods Mol Biol 2012; 806: 187-201. https://doi.org/10.1007/978-1-61779-367-7_13
  15. Li J, Kang SW, Kim JL, Sung HY, Kwun IS, Kang YH. Isoliquiritigenin entails blockade of TGF-${\beta}1$-SMAD signaling for retarding high glucose-induced mesangial matrix accumulation. J Agric Food Chem 2010; 58(5): 3205-3212. https://doi.org/10.1021/jf9040723
  16. Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood) 2008; 233(1): 4-11. https://doi.org/10.3181/0705-MR-134
  17. Kim DY, Kang MK, Park SH, Lee EJ, Kim YH, Oh H, et al. Eucalyptol ameliorates Snail1/${\beta}$-catenin-dependent diabetic disjunction of renal tubular epithelial cells and tubulointerstitial fibrosis. Oncotarget 2017; 8(63): 106190-106205. https://doi.org/10.18632/oncotarget.22311
  18. Shihata WA, Putra MR, Chin-Dusting JP. Is there a potential therapeutic role for caveolin-1 in fibrosis? Front Pharmacol 2017; 8: 567. https://doi.org/10.3389/fphar.2017.00567