Roasted licorice extracts dampen high glucose-induced mesangial hyperplasia and matrix deposition through blocking Akt activation and TGF-β signaling

Li, J.; Lee, Y.S.; Choi, J.-S.; Sung, H.-Y.; Kim, J.-K.; Lim, S.S.; Kang, Y.-H.

doi:10.1016/j.phymed.2010.02.004

« Previous Next »Phytomedicine
Volume 17, Issue 10 , Pages 800-810, August 2010

Roasted licorice extracts dampen high glucose-induced mesangial hyperplasia and matrix deposition through blocking Akt activation and TGF-β signaling

J. Li
- Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702 South Korea
Y.S. Lee
- Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702 South Korea
J.-S. Choi
- Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702 South Korea
H.-Y. Sung
- Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702 South Korea
J.-K. Kim
- Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Chuncheon, Kangwon-do, 200-702 South Korea
S.S. Lim
- Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702 South Korea
Y.-H. Kang
- Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702 South Korea
- Corresponding author: Tel.: 82332482132; fax: 82332541475.

published online 12 April 2010.

Abstract

Diabetic nephropathy (DN) characterized as nephrotic syndrome and diffuse glomerulosclerosis can cause renal failure and end-stage kidney disease. Expansion of mesangial matrix around capillaries in the kidney glomeruli is a prominent feature of DN. This study investigated whether licorice extracts inhibited mesangial cell (MC) proliferation and matrix accumulation induced by high glucose (HG). Human renal MC were cultured in media containing 5.5mM glucose plus 27.5mM mannitol as an osmotic control or 33mM glucose for 3 d in the presence of water or ethanol extracts from raw licorice (LW, LE) or roasted licorice (RLW, RLE). Non-polar components including glycyrrhetic acid were elevated during licorice roasting, whereas polar components soluble in water extracts were diminished. Exposure of cells to HG caused significant increases in collagen IV secretion and connective tissue growth factor (CTGF) expression, which was appeased by RLW and RLE at transcriptional levels. The inhibitory potency was high in the order of RLE ≥ RLW ≥ LE >>LW. Non-polar glycyrrhetic acid but not glycyrrhizin retarded HG-stimulated mesangial matrix deposition through diminishing CTGF expression. In addition, RLW and RLE but not LW modulated membrane type matrix metalloproteinase-1 (MT-1 MMP) expression, MMP-2 activity and tissue inhibitor of MMP-2 (TIMP-2), which facilitated the degradation of mesangial matrix. Furthermore, the augmented expression of CTGF and TIMP-2 in HG-exposed cells was mediated by Akt activation and TGF-β/Smad signaling through PKCβ2-responsive signaling pathways. However, HG-down-regulated MT-1 MMP expression was independent of activation of ERK1/2 and Akt when using their inhibitors of DB98059 (ERK1/2) and LY294002 (Akt) alone or in combination. These results demonstrate that extracts from roasted licorice may be highly potent therapeutic agents for the prevention and treatment of mesangial fibrosis and glomerulosclerosis leading to diabetes nephropathy due to longstanding diabetes mellitus.

Keywords: Connective tissue growth factor, High glucose, Licorice, Glycyrrhiza inflata, Mesangial matrix deposition, Akt activation, TGF-β signaling