Icariin attenuates high glucose-induced type IV collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor-β production and signalling through G protein-coupled oestrogen receptor 1.

Icariin has been shown to attenuate diabetic nephropathy in rats by decreasing transforming growth factor-β (TGF-β) and type IV collagen expression, but its mode of action in glomerular mesangial cells is uncertain. The present study aimed to investigate the effect of icariin on excess mesangial type IV collagen and fibronectin accumulation induced by high glucose, and to determine the mechanism underlying its protective effects. Under high-glucose conditions, icariin diminished type IV collagen and fibronectin accumulation, as well as TGF-β production in human and rat mesangial cells. Mesangial cells treated with icariin after TGF-β1 exposure expressed less type IV collagen and fibronectin than those without icariin treatment, suggesting inhibition by icariin of TGF-β1 downstream pathways. On TGF-β1 stimulation, icariin inhibited TGF-β canonical Smad signalling and extracellular signal-regulated kinase (ERK)1/2 signalling by decreasing Smad2/3 and ERK1/2 phosphorylation in a dose-dependent manner. U0126, which blocked the ERK1/2 pathway, exerted an additive effect on the icariin suppression of type IV collagen and fibronectin expression, enhancing the beneficial effects of icariin. The G protein-coupled oestrogen receptor 1 (GPER) antagonist, G-15, abolished the icariin-induced inhibition of type IV collagen, and fibronectin overproduction and TGF-β signalling. Treatment of cells with fulvestrant, a downregulator of the oestrogen receptor, enhanced the action of icariin. In conclusion, icariin decreased type IV collagen and fibronectin accumulation induced by high glucose in mesangial cells by inhibiting TGF-β production, as well as Smad and ERK signalling in a GPER-dependent manner.

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