Blocking protein phosphatase 2A signaling prevents endothelial-to-mesenchymal transition and renal fibrosis: a peptide-based drug therapy.
Blocking protein phosphatase 2A signaling prevents endothelial-to-mesenchymal transition and renal fibrosis: a peptide-based drug therapy.
复制标题
阻断蛋白磷酸酶 2A 信号传导可预防内皮间质转化和肾纤维化：基于肽的药物疗法
DOI：
10.1038/srep19821
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发表时间：
2016-01-25
影响因子：
4.6
通讯作者：
Xu G
中科院分区：
文献类型：
--
作者：
Deng Y;Guo Y;Liu P;Zeng R;Ning Y;Pei G;Li Y;Chen M;Guo S;Li X;Han M;Xu G
内皮-间充质转化(EndMT)促进成纤维细胞的形成，在肾间质纤维化中发挥重要作用。蛋白磷酸酶2A(PP2A)是真核细胞中一种主要的丝氨酸/苏氨酸蛋白磷酸酶，调节多种信号转导途径。然而，PP2A在EndMT中的意义还知之甚少。本研究旨在探讨PP2A在EndMT中的作用。我们证明，在内皮细胞(EC)获得EndMT表型的过程中，以及在梗阻性肾病(即UUO)的小鼠模型中，PP2A被激活。其特异性抑制剂抑制PP2A活性可阻止EC发生EndMT。重要的是，PP2A的激活依赖于PP2A催化亚基(PP2Ac)中127位的酪氨酸硝化。我们的肾脏保护策略是通过使用从PP2Ac衍生的模拟多肽与细胞穿透肽(CPP：TAT)结合来阻断酪氨酸127硝化以抑制PP2A的激活，称为TAT-Y127WT。TAT-Y127WT可拮抗转化生长因子-β-1诱导的EndMT。UUO小鼠给药后，肾EndMT水平显著改善，肾小管周围毛细血管密度保持不变，细胞外基质沉积减少。综上所述，这些结果表明，使用模拟多肽抑制PP2Ac硝化是肾纤维化EndMT的潜在预防策略。
Endothelial-to-mesenchymal transition (EndMT) contributes to the emergence of fibroblasts and plays a significant role in renal interstitial fibrosis. Protein phosphatase 2A (PP2A) is a major serine/threonine protein phosphatase in eukaryotic cells and regulates many signaling pathways. However, the significance of PP2A in EndMT is poorly understood. In present study, the role of PP2A in EndMT was evaluated. We demonstrated that PP2A activated in endothelial cells (EC) during their EndMT phenotype acquisition and in the mouse model of obstructive nephropathy (i.e., UUO). Inhibition of PP2A activity by its specific inhibitor prevented EC undergoing EndMT. Importantly, PP2A activation was dependent on tyrosine nitration at 127 in the catalytic subunit of PP2A (PP2Ac). Our renal-protective strategy was to block tyrosine127 nitration to inhibit PP2A activation by using a mimic peptide derived from PP2Ac conjugating a cell penetrating peptide (CPP: TAT), termed TAT-Y127WT. Pretreatment withTAT-Y127WT was able to prevent TGF-β1-induced EndMT. Administration of the peptide to UUO mice significantly ameliorated renal EndMT level, with preserved density of peritubular capillaries and reduction in extracellular matrix deposition. Taken together, these results suggest that inhibiting PP2Ac nitration using a mimic peptide is a potential preventive strategy for EndMT in renal fibrosis.