N-acetyl-seryl-aspartyl-lysyl-proline inhibits diabetes-associated kidney fibrosis and endothelial-mesenchymal transition.
N-acetyl-seryl-aspartyl-lysyl-proline inhibits diabetes-associated kidney fibrosis and endothelial-mesenchymal transition.
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DOI：
10.1155/2014/696475
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发表时间：
2014
影响因子：
--
通讯作者：
Koya D
中科院分区：
文献类型：
--
作者：
Nagai T;Kanasaki M;Srivastava SP;Nakamura Y;Ishigaki Y;Kitada M;Shi S;Kanasaki K;Koya D
内皮-间充质转化(EndMT)是成纤维细胞的重要来源。MicroRNA let-7具有抗EndMT的作用，成纤维细胞生长因子受体在microRNA let-7的表达中起重要作用。内源性抗纤维化多肽N-乙酰-丝氨酸-天冬氨酰-赖氨酸(AcSDKP)是血管紧张素转换酶(ACE)的底物。在这里，我们发现AcSDKP抑制EndMT，并表现出与成纤维细胞生长因子受体介导的抗纤维化程序相关的纤维化作用。与单独使用血管紧张素转换酶抑制剂治疗的CD-1糖尿病小鼠相比，传统的血管紧张素转换酶抑制剂加AcSDKP可改善糖尿病小鼠的肾脏纤维化并抑制EndMT。糖尿病动物内源性AcSDKP水平受到抑制。细胞因子诱导培养的内皮细胞形成EndMT；与AcSDKP共同孵育可抑制EndMT。糖尿病大鼠肾脏中microRNA let-7家族的表达受到抑制，AcSDKP的抗纤维化和抗EndMT作用与恢复microRNA let-7水平有关。在体内和体外，AcSDKP将糖尿病或细胞因子抑制的成纤维细胞生长因子受体表达/磷酸化恢复到正常水平。这些结果表明，AcSDKP是一种内源性抗纤维化分子，可能通过抑制与恢复成纤维细胞生长因子受体和microRNA let-7相关的EndMT来治疗糖尿病肾纤维化。
Endothelial-to-mesenchymal transition (EndMT) emerges as an important source of fibroblasts. MicroRNA let-7 exhibits anti-EndMT effects and fibroblast growth factor (FGF) receptor has been shown to be an important in microRNA let-7 expression. The endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a substrate of angiotensin-converting enzyme (ACE). Here, we found that AcSDKP inhibited the EndMT and exhibited fibrotic effects that were associated with FGF receptor-mediated anti-fibrotic program. Conventional ACE inhibitor plus AcSDKP ameliorated kidney fibrosis and inhibited EndMT compared to therapy with the ACE inhibitor alone in diabetic CD-1 mice. The endogenous AcSDKP levels were suppressed in diabetic animals. Cytokines induced cultured endothelial cells into EndMT; coincubation with AcSDKP inhibited EndMT. Expression of microRNA let-7 family was suppressed in the diabetic kidney; antifibrotic and anti-EndMT effects of AcSDKP were associated with the restoration of microRNA let-7 levels. AcSDKP restored diabetes- or cytokines-suppressed FGF receptor expression/phosphorylation into normal levels both in vivo and in vitro. These results suggest that AcSDKP is an endogenous antifibrotic molecule that has the potential to cure diabetic kidney fibrosis via an inhibition of the EndMT associated with the restoration of FGF receptor and microRNA let-7.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
8.8
作者：
Chen PY;Qin L;Barnes C;Charisse K;Yi T;Zhang X;Ali R;Medina PP;Yu J;Slack FJ;Anderson DG;Kotelianski V;Wang F;Tellides G;Simons M
通讯作者：
Simons M
影响因子：
4.8
作者：
Philp, D;Huff, T;Kleinman, HK
通讯作者：
Kleinman, HK
影响因子：
6
作者：
Li, Ping;Xiao, Hong D.;Fuchs, Sebastien
通讯作者：
Fuchs, Sebastien
影响因子：
3
作者：
Hashimoto, Y;Ohashi, R;Murata, S
通讯作者：
Murata, S