GdCl3 attenuates the glomerular sclerosis of streptozotocin (STZ) induced diabetic rats via inhibiting TGF-β/Smads signal pathway
GdCl3 attenuates the glomerular sclerosis of streptozotocin (STZ) induced diabetic rats via inhibiting TGF-β/Smads signal pathway
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GdCl3 通过抑制 TGF-β/Smads 信号通路减轻链脲佐菌素 (STZ) 诱导的糖尿病大鼠肾小球硬化
DOI：
10.1016/j.jphs.2019.06.008
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发表时间：
2020-02-01
影响因子：
3.5
通讯作者：
Wu, Suzhen
中科院分区：
文献类型：
--
作者：
Li, Jialin;Wu, Bing;Wu, Suzhen
糖尿病肾病（diabetic nephropathy，DN）是以肾小球肥大、肾小球基底膜（glomerular basement membrane，GBM）增厚、系膜扩张、肾纤维化等肾小球硬化为特征的最严重的终末期肾病。TGF-β/Smads信号通路在肾纤维化的发生发展中起着至关重要的作用。本研究发现，钙敏感受体（CaSR）激动剂GdCl_3可抑制TGF-β_1或高糖诱导的TGF-β_1/Smads信号通路的激活，从而减轻1型糖尿病大鼠肾小球系膜细胞和肾脏细胞外基质（ECM）的积聚。进一步的研究表明，GdCl_3可诱导CaSR和T β R Ⅱ结合，使这两种受体从细胞膜转位到细胞质，此时细胞膜上的T β R Ⅱ减少，对其配体TGF-β_1的刺激脱敏，从而阻断其下游因子Smad_2和Smad_3的激活，抑制系膜细胞ECM的表达。结论：GdCl 3可通过拮抗TGF-β/Smads信号通路减轻糖尿病大鼠系膜细胞ECM的积聚。(C)2019年，任作家。Elsevier B. V.代表日本药理学会制作和主办。
Diabetic nephropathy (DN) is the most serious end-stage renal disease which characterized by renal glomerular sclerosis including glomerular hypertrophy, glomerular basement membrane (GBM) thickening, mesangial expansion and renal fibrosis. TGF-beta/Smads signal pathway plays a crucial role in the development of renal fibrosis. In this study, we found that GdCl3 which was an agonist of Calcium-sensing receptor (CaSR) could repress the activation of TGF-beta/Smads signal pathway induced by TGF-beta 1 or high glucose and then alleviated the accumulation of extracellular matrix (ECM) in mesangial cells and the kidney of type1 diabetic rats. Further study indicated that GdCl3 could induce the binding of CaSR and T beta R II and then both of these two receptors translocated from cell membrane to cytoplasm, in this case, T beta R II on the cell membrane was decreased and then desensitized to the stimulation of its ligand TGF-beta 1, so that the activation of its downstream factors such as Smad2 and Smad3 were blocked, finally, ECM expression in mesangial cells were inhibited. We concluded that GdCl3 could alleviate the accumulation of ECM in mesangial cells via antagonizing TGF-beta/Smads signal pathway in diabetes mellitus. (C) 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.