Berberine suppresses high glucose-induced TGF-β1 and fibronectin synthesis in mesangial cells through inhibition of sphingosine kinase 1/AP-1 pathway.

Sphingosine kinase 1 (SphK1) pathway is critical in the pathogenesis of diabetic nephropathy. Recently, we found that berberine suppressed the activation of SphK1 pathway in diabetic kidney, protecting against diabetic nephropathy. The potential molecular mechanism, however, is still unknown. Here, we showed that berberine prevented the expression of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) and fibronectin (FN) in mesangial cells cultured by high glucose. Furthermore, berberine suppressed the activation of SphK1 pathway via inhibition of the activity and expression of SphK1 in mesangial cells cultured by high glucose. Surprisingly, berberine blocked the increased activity and expression of SphK1 in mesangial cells transfected by wild type SphK1 under normal glucose condition. However, berberine had no inhibitory effect on the recombinant human SphK1 protein. Finally, berberine markedly attenuated the high glucose-induced activator protein-1 (AP-1) activity in mesangial cells. Altogether, these data not only demonstrate that berberine is an important agent against diabetic nephropathy through inhibition of SphK1/AP-1 pathway, but also indicate that the inhibition of SphK1/AP-1 by berberine is independent of ambient glucose concentration.