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http://dx.doi.org/10.4163/jnh.2020.53.1.1

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

Kim, Dong Yeon (Department of Food Science and Nutrition, Hallym University)
Kang, Young-Hee (Department of Food Science and Nutrition, Hallym University)
Kang, Min-Kyung (Department of Food Science and Nutrition, Hallym University)

Publication Information

Journal of Nutrition and Health / v.53, no.1, 2020 , pp. 1-12 More about this Journal

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.

Keywords

nobiletin; diabetic nephropathy; glomerular fibrosis; $TGF-{\beta}1-Src-caveolin-1$ pathway;

Citations & Related Records

Reference

1	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. DOI
2	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. DOI
3	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.
4	Wilson HM, Stewart KN. Glomerular epithelial and mesangial cell culture and characterization. Methods Mol Biol 2012; 806: 187-201. DOI
5	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. DOI
6	Van Krieken R, Krepinsky JC. Caveolin-1 in the pathogenesis of diabetic nephropathy: potential therapeutic target? Curr Diab Rep 2017; 17(3): 19. DOI
7	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. DOI
8	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. DOI
9	Shihata WA, Putra MR, Chin-Dusting JP. Is there a potential therapeutic role for caveolin-1 in fibrosis? Front Pharmacol 2017; 8: 567. DOI
10	Ban CR, Twigg SM. Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag 2008; 4(3): 575-596. DOI
11	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. DOI
12	Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16 Suppl 1: S30-S33. DOI
13	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. DOI
14	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.
15	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. DOI
16	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. DOI
17	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. DOI
18	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. DOI