A cationic-independent mannose 6-phosphate receptor inhibitor (PXS64) ameliorates kidney fibrosis by inhibiting activation of transforming growth factor-β1.
A cationic-independent mannose 6-phosphate receptor inhibitor (PXS64) ameliorates kidney fibrosis by inhibiting activation of transforming growth factor-β1.
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一种不依赖于阳离子的甘露糖 6-磷酸受体抑制剂 (PXS64) 通过抑制转化生长因子-β1 的激活来改善肾纤维化。
DOI：
10.1371/journal.pone.0116888
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Saad S
中科院分区：
文献类型：
--
作者：
Zhang J;Wong MG;Wong M;Gross S;Chen J;Pollock C;Saad S
转化生长因子-β1（transforming growth factor-β 1，TGF-β1）的活性受其从潜伏型向活性型转化的调节。我们先前已经表明，该转化至少部分由阳离子非依赖性甘露糖6-磷酸受体（CI-M6 PR）介导，作为CI-M6 PR抑制剂，PXS-25在高糖条件下在人肾小管（HK-2）细胞中具有抗纤维化特性。然而，其临床应用受到生物利用度低的限制。我们的目的是确定PXS 25的前体药物PXS 64在肾纤维化的体外和体内模型中的作用。HK-2细胞暴露于潜伏的TGFβ1+/-PXS 64 48小时。测定促纤维化和促炎症标志物的mRNA和蛋白水平。使用7天单侧输尿管梗阻（UUO）模型，并研究以下实验组：（i）假手术，（ii）UUO，（iii）UUO +替米沙坦（iv）UUO + PSX 64。暴露于PXS 64的HK-2细胞降低了TGFβ介导的对IV型胶原、纤连蛋白、巨噬细胞趋化蛋白-1（MCP-1）和磷酸化-smad 2蛋白表达的影响，这与抑制潜伏性TGF-β1转化为活性TGF-β1一致。PXS 64处理的UUO小鼠与未处理的UUO小鼠相比，具有较低的肾小管间质纤维化指数、胶原IV和纤连蛋白和mRNA表达。此外，与未治疗的UUO动物相比，这些动物具有较低的MCP-1 mRNA表达，减少的炎性细胞浸润，如更少的CD 45、F4/80阳性细胞所示，以及减少的磷酸化Smad 2蛋白表达。我们的数据表明，PSX 64是一种有效的抗纤维化剂，通过抑制潜在的TGF-β1的活化。
The activity of transforming growth factor-β1 (TGF-β1) is regulated by its conversion from the latent to the active form. We have previously shown that the conversion is at least in part mediated by the cationic-independent mannose 6-phosphate receptor (CI-M6PR), as the CI-M6PR inhibitor, PXS-25 has anti-fibrotic properties in human kidney tubular (HK-2) cells under high glucose conditions. However, its clinical use is limited by low bioavailability. Our aim was to determine the effects of PXS64, a pro-drug of PXS25, in in vitro and in vivo models of renal fibrosis. HK-2 cells were exposed to latent TGFβ1+/- PXS64 for 48 hours. The mRNA and protein levels of pro-fibrotic and pro-inflammatory markers were determined. A 7 day unilateral ureteric obstruction (UUO) model was used and the following experimental groups were studied: (i) Sham operated, (ii) UUO, (iii) UUO + telmisartan (iv) UUO + PSX64. HK-2 cells exposed to PXS64 reduced TGFβ mediated effects on collagen IV, fibronectin, macrophage chemotactic protein-1 (MCP-1) and phospho-smad2 protein expression, consistent with inhibition of the conversion of latent to active TGF-β1. PXS 64 treated UUO mice had a lower tubulointerstitial fibrosis index, collagen IV and fibronectin protein and mRNA expression when compared to untreated UUO mice. In addition, these animals had lower MCP-1 mRNA expression, reduced inflammarory cell infiltrate, as indicated by fewer CD45, F4/80 positive cells, and reduced phospho-Smad2 protein expression when compared to untreated UUO animals. Our data demonstrates that PSX64 is an effective anti-fibrotic agent by inhibiting the activation of latent TGF-β1.
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影响因子：
7
作者：
Czupalla, C;Mansukoski, H;Hoflack, B
通讯作者：
Hoflack, B
影响因子：
4.8
作者：
Hayashida, T;deCaestecker, M;Schnaper, HW
通讯作者：
Schnaper, HW
DOI：
10.1083/jcb.106.5.1659
发表时间：
1988-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lyons RM;Keski-Oja J;Moses HL
通讯作者：
Moses HL
影响因子：
6.2
作者：
Djamali A;Vidyasagar A;Yagci G;Huang LJ;Reese S
通讯作者：
Reese S
影响因子：
6.4
作者：
Jones-Carson, J;Fantuzzi, G;Vazquez-Torres, A
通讯作者：
Vazquez-Torres, A