title: Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition.
abstract: 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 5.5 mM glucose, 27.5 mM mannitol (as an osmotic control), or 33 mM glucose (HG) in the absence and presence of 1-20 μM chrysin for 72 h. 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.
  
  
  CONCLUSIONS
  • 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.
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702, Republic of Korea.
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Kang
authors.forename: Sin-Hye
authors.initials: SH
authors.lastname: Park
authors.forename: Yean-Jung
authors.initials: YJ
authors.lastname: Choi
authors.forename: Daekeun
authors.initials: D
authors.lastname: Shin
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005355:Fibrosis / Q000188:drug therapy* / Q000473:pathology; D005419:Flavonoids / Q000627:therapeutic use*; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology; D007684:Kidney Tubules / Q000166:cytology / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin / Q000096:biosynthesis; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D015820:Cadherins; D005419:Flavonoids; D062793:Occludin; C568986:Ocln protein, mouse; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C043561:chrysin; D003094:Collagen; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2