College of Pharmacy, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China.
School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China.
J Pharmacol Sci. 2020 Feb;142(2):41-49. doi: 10.1016/j.jphs.2019.06.008. Epub 2019 Aug 6.
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-β/Smads signal pathway plays a crucial role in the development of renal fibrosis. In this study, we found that GdCl which was an agonist of Calcium-sensing receptor (CaSR) could repress the activation of TGF-β/Smads signal pathway induced by TGF-β1 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 GdCl could induce the binding of CaSR and TβR II and then both of these two receptors translocated from cell membrane to cytoplasm, in this case, TβR II on the cell membrane was decreased and then desensitized to the stimulation of its ligand TGF-β1, 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 GdCl could alleviate the accumulation of ECM in mesangial cells via antagonizing TGF-β/Smads signal pathway in diabetes mellitus.
糖尿病肾病（DN）是最严重的终末期肾脏疾病，其特征为包括肾小球肥大、肾小球基底膜（GBM）增厚、系膜扩张和肾纤维化在内的肾小球硬化。TGF-β/Smads 信号通路在肾纤维化的发展中起着关键作用。在这项研究中，我们发现 GdCl（一种钙敏感受体（CaSR）激动剂）能够抑制 TGF-β1 或高糖诱导的 TGF-β/Smads 信号通路的激活，从而减轻系膜细胞和 1 型糖尿病大鼠肾脏中细胞外基质（ECM）的积累。进一步的研究表明，GdCl 能够诱导 CaSR 和 TβR II 的结合，然后这两种受体从细胞膜向细胞质转位，在这种情况下，细胞膜上的 TβR II 减少，对其配体 TGF-β1 的刺激脱敏，从而阻断其下游因子如 Smad2 和 Smad3 的激活，最终抑制系膜细胞中 ECM 的表达。我们得出结论，GdCl 能够通过拮抗糖尿病中的 TGF-β/Smads 信号通路来减轻系膜细胞中 ECM 的积累。
