The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase
The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase
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DOI：
10.1152/ajprenal.00562.2015
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发表时间：
2016-05-15
影响因子：
4.2
通讯作者：
Carretero, Oscar A.
中科院分区：
文献类型：
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作者：
Kumar, Nitin;Nakagawa, Pablo;Carretero, Oscar A.
N-乙酰-丝氨酰-赖氨酰-脯氨酸（Ac-SDKP）是一种具有抗炎和抗纤维化特性的天然四肽。以前，我们已经表明脯氨酰寡肽酶（POP）参与从胸腺肽-β 4（T β 4）释放Ac-SDKP。然而，POP只能水解短于30个氨基酸的肽，而T β 4长43个氨基酸。这表明在POP水解发生之前，T β 4被另一种肽酶水解，该肽酶释放具有少于30个氨基酸的NH 2-末端中间肽。我们的肽酶数据库搜索指出，meprin-α金属蛋白酶作为一个潜在的候选人。因此，我们假设，在POP水解之前，T β 4被meprin-alpha水解。在体外，我们发现，T β 4与meprin-alpha和POP孵育释放Ac-SDKP，而当T β 4与meprin-alpha或POP单独孵育时，没有Ac-SDKP释放。用大鼠肾匀浆孵育T β 4显著释放Ac-SDKP，其被meprin-alpha抑制剂actinonin阻断。此外，与野生型小鼠相比，来自meprin-alpha敲除（KO）小鼠的肾脏显示出显著较低的基础Ac-SDKP量。来自meprin-alpha KO小鼠的肾匀浆未能从T β 4释放Ac-SDKP。在体内，我们观察到用ACE抑制剂卡托普利治疗的大鼠增加了Ac-SDKP的血浆浓度，而这被同时给予放线菌素抑制（载体，3.1 +/- 0.2 nmol/l;卡托普利，15.1 +/- 0.7 nmol/l;卡托普利+放线菌素，6.1 +/- 0.3 nmol/l; P < 0.005）。放线菌素处理后，尿Ac-SDKP获得了类似的结果。我们得出结论，从T β 4释放Ac-SDKP是由涉及meprin-alpha和POP的连续水解介导的。
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with anti-inflammatory and antifibrotic properties. Previously, we have shown that prolyl oligopeptidase (POP) is involved in the Ac-SDKP release from thymosin-beta 4 (T beta 4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and T beta 4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, T beta 4 is hydrolyzed by another peptidase that releases NH2-terminal intermediate peptide( s) with fewer than 30 amino acids. Our peptidase database search pointed out meprin-alpha metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, T beta 4 is hydrolyzed by meprin-alpha. In vitro, we found that the incubation of T beta 4 with both meprin-alpha and POP released Ac-SDKP, whereas no Ac-SDKP was released when T beta 4 was incubated with either meprin-alpha or POP alone. Incubation of T beta 4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-alpha inhibitor actinonin. In addition, kidneys from meprin-alpha knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-alpha KO mice failed to release Ac-SDKP from T beta 4. In vivo, we observed that rats treated with the ACE inhibitor captopril increased plasma concentrations of Ac-SDKP, which was inhibited by the coadministration of actinonin (vehicle, 3.1 +/- 0.2 nmol/l; captopril, 15.1 +/- 0.7 nmol/l; captopril + actinonin, 6.1 +/- 0.3 nmol/l; P < 0.005). Similar results were obtained with urinary Ac-SDKP after actinonin treatment. We conclude that release of Ac-SDKP from T beta 4 is mediated by successive hydrolysis involving meprin-alpha and POP.