황금탕의 족돌기세포에서의 EMT 억제 효능
Hwanggeum-tang Water Extracts Suppress TGF-β1 Induced EMT in Podocyte
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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.
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.
참고문헌 (31)
- "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", Abstracts of the 7th Lung Cancer Biology Workshop, 34(3), pp.S1~S26 (2001)
- Liu YH, "New Insights into Epithelial-Mesenchymal Transition in Kidney Fibrosis", Journal of the American Society of Nephrology, 21(2), pp.212~222 (2010)
- Reidy K, "Epithelial-Mesenchymal Transition and Podocyte Loss in Diabetic Kidney Disease", American Journal of Kidney Diseases, 54(4), pp.590~593 (2009)
- Ziyadeh FN, "Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy", Current diabetes reviews, 4(1), pp.39~45 (2008)
- Li JJ, "Podocyte biology in diabetic nephropathy", Kidney international Supplement, (106), pp.S36~S42 (2007)
- Ilatovskaya DV, "Podocyte injury in diabetic nephropathy : implications of angiotensin II-dependent activation of TRPC channels", Scientific reports, 5, pp.17637~ (2015)
- 정상훈, "黃芩湯 추출물이 THP-1 세포에서 당화종말산물에 의한 염증반응에 미치는 효과", 동의생리병리학회지, 26(2), pp.147~154 (2012), 한의병리학회[DOI]
- Schena FP, "Pathogenetic mechanisms of diabetic nephropathy", Journal of the American Society of Nephrology : JASN, 16(Suppl 1), pp.S30~S33 (2005)
- Brownlee M, "Biochemistry and molecular cell biology of diabetic complications", Nature, 414(6865), pp.813~820 (2001)
- Mason RM, "Extracellular matrix metabolism in diabetic nephropathy", Journal of the American Society of Nephrology : JASN, 14(5), pp.1358~1373 (2003)
- Gilbert RE, "The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury?", Kidney Int, 56(5), pp.1627~1637 (1999)
- Gruden G, "Insight on the pathogenesis of diabetic nephropathy from the study of podocyte and mesangial cell biology", Current diabetes reviews, 1(1), pp.27~40 (2005)
- Dai HR, "Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy", Journal of diabetes research (2017)
- Ying QD, "Molecular mechanisms involved in podocyte EMT and concomitant diabetic kidney diseases : an update", Renal failure, 39(1), pp.474~483 (2017)
- Pagtalunan ME, "Podocyte loss and progressive glomerular injury in type II diabetes", Journal of Clinical Investigation, 99(2), pp.342~348 (1997)
- Dai H, "Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy", Journal of diabetes research, 2017, pp.2615286~ (2017)
- Iwano M, "Evidence that fibroblasts derive from epithelium during tissue fibrosis", Journal of Clinical Investigation, 110(3), pp.341~350 (2002)
- Ng YY, "Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5", 6 nephrectomized rats, 1998, pp.54(3), 864~876
- Rastaldi MP, "Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies", Kidney International, 62(1), pp.137~146 (2002)
- Burns WC, "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, 17(9), pp.2484~2494 (2006)
- Loeffler I, "Transforming growth factor-beta and the progression of renal disease", Nephrol Dial Transpl, 29, pp.I37~I45 (2014)
- Kitamura M, "TGF-beta and glomerulonephritis : Anti-inflammatory versus prosclerotic actions", Nephrol Dial Transpl, 12(4), pp.669~679 (1997)
- Lopez-Hernandez FJ, "Role of TGF-beta in chronic kidney disease : an integration of tubular, glomerular and vascular effects", Cell and tissue research, 347(1), pp.141~154 (2012)
- Han DC, "Therapy with antisense TGF-beta1 oligodeoxynucleotides reduces kidney weight and matrix mRNAs in diabetic mice", American journal of physiology Renal physiology, 278(4), pp.F628~F634 (2000)
- Wrana JL, "Mechanism of activation of the TGF-beta receptor", Nature, 370(6488), pp.341~347 (1994)
- Lamouille S, "Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway", J Cell Biol, 178(3), pp.437~451 (2007)
- Wullschleger S, "TOR signaling in growth and metabolism", Cell, 124(3), pp.471~484 (2006)
- Zhou HY, "Current development of the second generation of mTOR inhibitors as anticancer agents", Chin J Cancer, 31(1), pp.8~18 (2012)
- Godel M, "Role of mTOR in podocyte function and diabetic nephropathy in humans and mice", Journal of Clinical Investigation, 121(6), pp.2197~2209 (2011)
- Inoki K, "mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice", Journal of Clinical Investigation, 121(6), pp.2181~2196 (2011)
- Inoki K, "TSC2 mediates cellular energy response to control cell growth and survival", Cell, 115(5), pp.577~590 (2003)