Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Eur J Pharmacol. 2012 Dec 15;697(1-3):165-72. doi: 10.1016/j.ejphar.2012.10.003. Epub 2012 Oct 16.
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.
鞘氨醇激酶 1（SphK1）通路在糖尿病肾病的发病机制中起关键作用。最近，我们发现小檗碱抑制糖尿病肾脏中 SphK1 通路的激活，从而防止糖尿病肾病。然而，其潜在的分子机制尚不清楚。在这里，我们表明小檗碱可防止高糖培养的系膜细胞中α-平滑肌肌动蛋白（α-SMA）、转化生长因子-β1（TGF-β1）和纤连蛋白（FN）的表达。此外，小檗碱通过抑制高糖培养的系膜细胞中 SphK1 的活性和表达来抑制 SphK1 通路的激活。令人惊讶的是，小檗碱可阻断在正常葡萄糖条件下转染野生型 SphK1 的系膜细胞中 SphK1 活性和表达的增加。然而，小檗碱对重组人 SphK1 蛋白没有抑制作用。最后，小檗碱可显著减弱高糖诱导的系膜细胞中激活蛋白-1（AP-1）的活性。总之，这些数据不仅表明小檗碱通过抑制 SphK1/AP-1 通路是一种重要的抗糖尿病肾病药物，而且还表明小檗碱对 SphK1/AP-1 的抑制作用不依赖于环境葡萄糖浓度。
