Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, P.R. China.
Biochemistry Department, Gannan Medical University, Ganzhou, P.R. China.
Biosci Rep. 2017 Oct 27;37(5). doi: 10.1042/BSR20171061. Print 2017 Oct 31.
Little is known about the cross-talk between parathyroid hormone (PTH) related protein (PTHrP) and TGF-β1 in mesangial cells (MCs). Our results showed that PTHrP treatment (≤3 h) induced internalization of PTH1R (PTH/PTHrP receptor)-TβRII (TGF-β type 2 receptor) complex and suppressed TGF-β1-mediated Smad2/3 activation and fibronectin (FN) up-regulation. However, prolonged PTHrP treatment (12-48 h) failed to induce PTH1R-TβRII association and internalization. Total protein levels of PTH1R and TβRII were unaffected by PTHrP treatment. These results suggest that internalization of PTH1R and TβRII after short PTHrP treatment might not lead to their proteolytic destruction, allowing the receptors to be recycled back to the plasma membrane during prolonged PTHrP exposure. Receptor re-expression at the cell surface allows PTHrP to switch from its initial inhibitory effect to promote induction of FN. Our study thus demonstrates the dual roles of PTHrP on TGF-β1 signaling and FN up-regulation for the first time in glomerular MCs. These data also provided new insights to guide development of therapy for diabetic kidney disease (DKD).
关于甲状旁腺激素（PTH）相关蛋白（PTHrP）与转化生长因子-β1（TGF-β1）在肾小球系膜细胞（MCs）中的相互作用知之甚少。我们的研究结果表明，PTHrP 处理（≤3 小时）诱导 PTH1R（PTH/PTHrP 受体）-TβRII（TGF-β 型 2 受体）复合物内化，并抑制 TGF-β1 介导的 Smad2/3 激活和纤维连接蛋白（FN）上调。然而，延长 PTHrP 处理（12-48 小时）未能诱导 PTH1R-TβRII 结合和内化。PTHrP 处理对 PTH1R 和 TβRII 的总蛋白水平没有影响。这些结果表明，短时间 PTHrP 处理后 PTH1R 和 TβRII 的内化可能不会导致其蛋白水解破坏，从而允许受体在长时间 PTHrP 暴露期间被回收回质膜。受体在细胞表面的重新表达使 PTHrP 能够从其初始抑制作用转变为促进 FN 的诱导。因此，我们的研究首次在肾小球 MCs 中证明了 PTHrP 在 TGF-β1 信号传导和 FN 上调中的双重作用。这些数据还为指导糖尿病肾病（DKD）的治疗方法的发展提供了新的见解。
