Department of Traditional Chinese Medicine and Endocrinology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Int J Mol Med. 2013 Jul;32(1):151-7. doi: 10.3892/ijmm.2013.1377. Epub 2013 May 10.
High glucose levels can induce mesangial cell proliferation and extracellular matrix (ECM) accumulation through the type I activin receptor-like kinase 5 (ALK5) signaling pathway. Salt-inducible kinase 1 (SIK1) prevents fibrosis by downregulating ALK5, while the expression level of the SIK1 protein itself is downregulated by glucose in neuronal cells following ischemia. In this study, we investigated the correlation between SIK1 and the ALK5 signaling pathway in a rat glomerular mesangial cell line (HBZY-1 cells). We found that high glucose levels downregulated the expression level of SIK1 and suppressed the phosphorylation of SIK1 at Thr-182. The downregulation of SIK1 by high glucose was accompanied by the activation of the ALK5 signaling pathway, while the overexpression of SIK1 in the HBZY-1 cells resulted in a decrease in the ALK5 protein level, as well in the levels of its downstream targets, including fibronectin and plasminogen activator inhibitor type I. In conclusion, high glucose may activate the ALK5 signaling pathway by downregulating SIK1, and SIK1 may be a protective factor against cellular proliferation and ECM accumulation in glomerular mesangial cells under high glucose conditions.
高血糖可通过 I 型激活素受体样激酶 5（ALK5）信号通路诱导系膜细胞增殖和细胞外基质（ECM）积聚。盐诱导激酶 1（SIK1）通过下调 ALK5 来防止纤维化，而在神经元细胞缺血后，葡萄糖会下调 SIK1 蛋白本身的表达水平。在这项研究中，我们研究了 SIK1 与大鼠肾小球系膜细胞系（HBZY-1 细胞）中 ALK5 信号通路之间的相关性。我们发现高葡萄糖水平下调了 SIK1 的表达水平，并抑制了 SIK1 在 Thr-182 位点的磷酸化。高葡萄糖引起的 SIK1 下调伴随着 ALK5 信号通路的激活，而在 HBZY-1 细胞中过表达 SIK1 导致 ALK5 蛋白水平以及其下游靶标，包括纤维连接蛋白和纤溶酶原激活物抑制剂 1 的水平降低。总之，高葡萄糖可能通过下调 SIK1 来激活 ALK5 信号通路，而 SIK1 可能是高葡萄糖条件下肾小球系膜细胞增殖和 ECM 积聚的保护因子。
