caa a22 4500 605543224 CHVBK 20210128100925.0 cr unu---uuuuu 210128e20150701xx s 000 0 eng 10.1007/s00109-015-1301-3 doi (NATIONALLICENCE)springer-10.1007/s00109-015-1301-3 Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition [Elektronische Daten] [Min-Kyung Kang, Sin-Hye Park, Yean-Jung Choi, Daekeun Shin, Young-Hee Kang] Renal fibrosis is a crucial event in the pathogenesis of diabetic nephropathy (DN). The process known as epithelial to mesenchymal transition (EMT) contributes to the accumulation of matrix proteins in kidneys, in which renal tubular epithelial cells play an important role in progressive renal fibrosis. The current study investigated that chrysin (5,7-dihydroxyflavone) present in bee propolis and herbs, inhibited renal tubular EMT and tubulointerstitial fibrosis due to chronic hyperglycemia. Human renal proximal tubular epithelial cells (RPTEC) were incubated in media containing 5.5mM glucose, 27.5mM mannitol (as an osmotic control), or 33mM glucose (HG) in the absence and presence of 1-20μM chrysin for 72h. Chrysin significantly inhibited high glucose-induced renal EMT through blocking expression of the mesenchymal markers vimentin, α-smooth muscle actin, and fibroblast-specific protein-1 in RPTEC and db/db mice. Chrysin reversed the HG-induced down-regulation of the epithelial marker E-cadherin and the HG-enhanced N-cadherin induction in RPTEC. In addition, chrysin inhibited the production of collagen IV in tubular cells and the deposition of collagen fibers in mouse kidneys. Furthermore, chrysin blocked tubular cell migration concurrent with decreasing matrix metalloproteinase-2 activity, indicating epithelial cell derangement and tubular basement membrane disruption. Chrysin restored the induction of the tight junction proteins Zona occludens protein-1 (ZO-1) and occludin downregulated in diabetic mice. Chrysin inhibited renal tubular EMT-mediated tubulointerstitial fibrosis caused by chronic hyperglycemia. Therefore, chrysin may be a potent renoprotective agent for the treatment of renal fibrosis-associated DN. Key messages: • Glucose increases renal tubular epithelial induction of vimentin, α-SMA and FSP-1. • Glucose enhances renal EMT by blocking tubular epithelial E-cadherin expression. • Chrysin inhibits tubular EMT-mediated tubulointerstitial fibrosis in mouse kidneys. • Chrysin restores renal tubular induction of ZO-1 and occludin downregulated in diabetic mice. • Chrysin blocks glucose-induced renal tubular cell migration with reducing MMP-2 activity. Springer-Verlag Berlin Heidelberg, 2015 Chrysin nationallicence Diabetic nephropathy nationallicence Epithelial to mesenchymal transition nationallicence High glucose nationallicence Tubulointerstitial fibrosis nationallicence CTGF : Connective tissue growth factor nationallicence DN : Diabetic nephropathy nationallicence ECM : Extracellular matrix nationallicence EMT : Epithelial to mesenchymal transition nationallicence FSP-1 : Fibroblast-specific protein nationallicence MT1-MMP : Membrane type 1-matrix metalloproteinase nationallicence RPTEC : Human renal proximal tubular epithelial cells nationallicence α-SMA : α-smooth muscle actin nationallicence TIMP-2 : Tissue inhibitor of metalloproteinase-2 nationallicence ZO-1 : Zona occludens protein-1 nationallicence Kang Min-Kyung Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut Park Sin-Hye Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut Choi Yean-Jung Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut Shin Daekeun Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut Kang Young-Hee Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/7(2015-07-01), 759-772 0946-2716 93:7<759 2015 93 109 https://doi.org/10.1007/s00109-015-1301-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1301-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kang Min-Kyung Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut NATIONALLICENCE 700 1- Park Sin-Hye Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut NATIONALLICENCE 700 1- Choi Yean-Jung Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut NATIONALLICENCE 700 1- Shin Daekeun Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut NATIONALLICENCE 700 1- Kang Young-Hee Department of Food and Nutrition, Hallym University, 200-702, Chuncheon, Kangwon-do, Republic of Korea aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/7(2015-07-01), 759-772 0946-2716 93:7<759 2015 93 109