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Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition

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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.

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.

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Abbreviations

CTGF:

Connective tissue growth factor

DN:

Diabetic nephropathy

ECM:

Extracellular matrix

EMT:

Epithelial to mesenchymal transition

FSP-1:

Fibroblast-specific protein

MT1-MMP:

Membrane type 1-matrix metalloproteinase

RPTEC:

Human renal proximal tubular epithelial cells

α-SMA:

α-smooth muscle actin

TIMP-2:

Tissue inhibitor of metalloproteinase-2

ZO-1:

Zona occludens protein-1

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Acknowledgments

This research was financially supported by the Ministry of Education, Science Technology (MEST) and National Research Foundation of Korea (NRF) through the Human Resource Training Project for Regional Innovation (2014028986) and by the National Research Foundation of Korea (2014028986). This work was also supported by the NRF grant funded by the Korean government (201 2R1A2A2A01012946). The abstract of this work was presented in poster format in the Experimental Biology 2014.

Conflict of interest

The authors declare that they have no conflict of interests.

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  1. Department of Food and Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702, Republic of Korea

    Min-Kyung Kang, Sin-Hye Park, Yean-Jung Choi, Daekeun Shin & Young-Hee Kang

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Kang, MK., Park, SH., Choi, YJ. et al. Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition. J Mol Med 93, 759–772 (2015). https://doi.org/10.1007/s00109-015-1301-3

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  • DOI: https://doi.org/10.1007/s00109-015-1301-3

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