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http://dx.doi.org/10.15188/kjopp.2020.04.34.2.61

Hwanggeum-tang Water Extracts Suppress TGF-β1 Induced EMT in Podocyte  

Shin, Sang Woo (Division of Applied Medicine, School of Korean Medicine, Pusan National University)
Jeong, Han-Sol (Division of Applied Medicine, School of Korean Medicine, Pusan National University)
Publication Information
Journal of Physiology & Pathology in Korean Medicine / v.34, no.2, 2020 , pp. 61-66 More about this Journal
Abstract
Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells lose their characters and acquire the properties of mesenchymal cells. EMT has been reported to exert an essential role in embryonic development. Recently, EMT has emerged as a pivotal mechanism in the metastasis of cancer and the fibrosis of chronic diseases. In particular, EMT is drawing attention as a mechanism of renal fibrosis in chronic kidney diseases such as diabetic nephropathy. In this study, we developed an EMT model by treating TGF-β1 on the podocytes, which play a key role in the renal glomerular filtration. This study explored the effects of Hwanggeum-tang (HGT) recorded in Dongeuibogam as being able to be used for the treatment of Sogal whose concept had been applied to Diabetes Mellitus (DM), on the TGF-β1-induced podocyte EMT. HGT suppressed the expression of vimentin and α-SMA, the EMT marker, in the human podocytes stimulated by TGF-β1. However, HGT increased the expression of ZO-1 and nephrin. Interestingly, HGT selectively inhibited the mTOR pathway rather than the classical Smad pathway. HGT also activated the AMPK signaling. HGT's inhibitory effect on the podocyte EMT through regulation of the mTOR pathway was achieved through the activation of AMPK, which was confirmed by comparison with cells treated with compound C (CC), an inhibitor of AMPK signaling. In conclusion, HGT can be applied to the renal fibrosis by preventing TGF-β1-induced EMT of podocytes through AMPK activation and mTOR inhibition.
Keywords
Epithelial-mesenchymal transition; Kidney fibrosis; mTOR; AMPK;
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1 Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471-84.   DOI
2 Abstracts of the 7th Lung Cancer Biology Workshop: Molecular biology and pharmacogenetic research in the treatment of lung cancer, Barcelona, Spain, April 30 May 3, 2001. Lung Cancer. 2001;34(3):S1-S26.   DOI
3 Liu YH. New Insights into Epithelial-Mesenchymal Transition in Kidney Fibrosis. Journal of the American Society of Nephrology. 2010;21(2):212-22.   DOI
4 Reidy K, Susztak K. Epithelial-Mesenchymal Transition and Podocyte Loss in Diabetic Kidney Disease. American Journal of Kidney Diseases. 2009;54(4):590-3.   DOI
5 Ziyadeh FN, Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Current diabetes reviews. 2008;4(1):39-45.   DOI
6 Li JJ, Kwak SJ, Jung DS, Kim JJ, Yoo TH, Ryu DR, et al. Podocyte biology in diabetic nephropathy. Kidney international Supplement. 2007(106):S36-42.
7 Ilatovskaya DV, Levchenko V, Lowing A, Shuyskiy LS, Palygin O, Staruschenko A. Podocyte injury in diabetic nephropathy: implications of angiotensin II-dependent activation of TRPC channels. Scientific reports. 2015;5:17637.   DOI
8 SH Jeong, KG Lee, CH Lee, SR Lee, JE Kim, KT Ha, et al. Effects of Hwanggeum-tang Water Extract on the expression of pro-inflammatory responses elicited by advanced glycation end products in THP-1 cells. Korean J. Oriental Physiology & Pathology. 2012:26(2):147-154.
9 Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. Journal of the American Society of Nephrology : JASN. 2003;14(5):1358-73.   DOI
10 Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813-20.   DOI
11 Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int. 1999;56(5):1627-37.   DOI
12 Gruden G, Perin PC, Camussi G. Insight on the pathogenesis of diabetic nephropathy from the study of podocyte and mesangial cell biology. Current diabetes reviews. 2005;1(1):27-40.   DOI
13 Dai HR, Liu QQ, Liu BL. Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy. Journal of diabetes research. 2017.
14 Ying QD, Wu GZ. Molecular mechanisms involved in podocyte EMT and concomitant diabetic kidney diseases: an update. Renal failure. 2017;39(1):474-83.   DOI
15 Pagtalunan ME, Miller PL, JumpingEagle S, Nelson RG, Myers BD, Rennke HG, et al. Podocyte loss and progressive glomerular injury in type II diabetes. Journal of Clinical Investigation. 1997;99(2):342-8.   DOI
16 Rastaldi MP, Ferrario F, Giardino L, Dell'Antonio G, Grillo C, Grillo P, et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney International. 2002;62(1):137-46.   DOI
17 Dai H, Liu Q, Liu B. Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy. Journal of diabetes research. 2017;2017:2615286.
18 Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. Journal of Clinical Investigation. 2002;110(3):341-50.   DOI
19 Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. Journal of the American Society of Nephrology : JASN. 2005;16 Suppl 1:S30-3.   DOI
20 Ng YY, Huang TP, Yang WC, Chen ZP, Yang AH, Mu W, et al. Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney International. 1998;54(3):864-76.   DOI
21 Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, et al. Connective tissue growth factor plays an important role in advance glycation end product-induced tubular epithelial-to-mesenchymal transition: Implications for diabetic renal disease. Journal of the American Society of Nephrology. 2006;17(9):2484-94.   DOI
22 Loeffler I, Wolf G. Transforming growth factor-beta and the progression of renal disease. Nephrol Dial Transpl. 2014;29:I37-I45.
23 Kitamura M, Suto TS. TGF-beta and glomerulonephritis: Anti-inflammatory versus prosclerotic actions. Nephrol Dial Transpl. 1997;12(4):669-79.   DOI
24 Lamouille S, Derynck R. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol. 2007;178(3):437-51.   DOI
25 Lopez-Hernandez FJ, Lopez-Novoa JM. Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell and tissue research. 2012;347(1):141-54.   DOI
26 Han DC, Hoffman BB, Hong SW, Guo J, Ziyadeh FN. Therapy with antisense TGF-beta1 oligodeoxynucleotides reduces kidney weight and matrix mRNAs in diabetic mice. American journal of physiology Renal physiology. 2000;278(4):F628-34.   DOI
27 Wrana JL, Attisano L, Wieser R, Ventura F, Massague J. Mechanism of activation of the TGF-beta receptor. Nature. 1994;370(6488):341-7.   DOI
28 Inoki K, Mori H, Wang JY, Suzuki T, Hong SK, Yoshida S, et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. Journal of Clinical Investigation. 2011;121(6):2181-96.   DOI
29 Zhou HY, Huang SL. Current development of the second generation of mTOR inhibitors as anticancer agents. Chin J Cancer. 2012;31(1):8-18.
30 Godel M, Hartleben B, Herbach N, Liu SY, Zschiedrich S, Lu S, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. Journal of Clinical Investigation. 2011;121(6):2197-209.   DOI
31 Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577-90.   DOI