Effect of Antifibrotic MicroRNAs Crosstalk on the Action of N-acetyl-seryl-aspartyl-lysyl-proline in Diabetes-related Kidney Fibrosis.
Effect of Antifibrotic MicroRNAs Crosstalk on the Action of N-acetyl-seryl-aspartyl-lysyl-proline in Diabetes-related Kidney Fibrosis.
复制标题
抗纤维化 MicroRNA 串扰对 N-乙酰基-丝氨酰-天冬氨酰-赖氨酰-脯氨酸在糖尿病相关肾纤维化中作用的影响。
DOI：
10.1038/srep29884
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发表时间：
2016-07-18
影响因子：
4.6
通讯作者：
Koya D
中科院分区：
文献类型：
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作者：
Srivastava SP;Shi S;Kanasaki M;Nagai T;Kitada M;He J;Nakamura Y;Ishigaki Y;Kanasaki K;Koya D
N-乙酰-丝氨酸-天冬氨酰-赖氨酸(AcSDKP)是一种内源性抗纤维化多肽。我们发现，抑制AcSDKP和诱导二肽基肽酶-4(DPP-4)与肾脏抗纤维化微核糖核酸(MiR)S水平不足有关，对于了解糖尿病肾脏纤维化的机制是必不可少的。分析链脲佐菌素(STZ)诱导的糖尿病小鼠品系，肾脏纤维化的糖尿病CD-1小鼠可以通过抑制AcSDKP和抗纤维化miR(miR-29S和miR-let-7S)以及通过显著诱导DPP-4蛋白表达/活性和内皮向间充质转化而与较少纤维化的糖尿病129Sv小鼠区分开来。在糖尿病小鼠CD-1中，这些变化均被AcSDKP治疗逆转。对培养内皮细胞的转染研究表明，miR-29S和miR-let-7S对间充质激活程序的串扰调节；这种双向调节可能在维持AcSDKP的抗纤维化程序中发挥重要作用。最后，我们观察到，在纤维化的小鼠中，AcSDKP的抑制与干扰素-γ和转化生长因子-β信号的诱导有关，这两个信号是破坏抗纤维化MIR串扰的关键分子通路。本研究提供了AcSDKP通过抗纤维化MIR的生理相关的抗纤维化作用；恢复这种抗纤维化程序可能在抗击糖尿病肾纤维化方面显示出潜在的作用。
N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous antifibrotic peptide. We found that suppression of AcSDKP and induction of dipeptidyl peptidase-4 (DPP-4), which is associated with insufficient levels of antifibrotic microRNA (miR)s in kidneys, were imperative to understand the mechanisms of fibrosis in the diabetic kidneys. Analyzing streptozotocin (STZ)-induced diabetic mouse strains, diabetic CD-1 mice with fibrotic kidneys could be differentiated from less-fibrotic diabetic 129Sv mice by suppressing AcSDKP and antifibrotic miRs (miR-29s and miR-let-7s), as well as by the prominent induction of DPP-4 protein expression/activity and endothelial to mesenchymal transition. In diabetic CD-1 mice, these alterations were all reversed by AcSDKP treatment. Transfection studies in culture endothelial cells demonstrated crosstalk regulation of miR-29s and miR-let-7s against mesenchymal activation program; such bidirectional regulation could play an essential role in maintaining the antifibrotic program of AcSDKP. Finally, we observed that AcSDKP suppression in fibrotic mice was associated with induction of both interferon-γ and transforming growth factor-β signaling, crucial molecular pathways that disrupt antifibrotic miRs crosstalk. The present study provides insight into the physiologically relevant antifibrotic actions of AcSDKP via antifibrotic miRs; restoring such antifibrotic programs could demonstrate potential utility in combating kidney fibrosis in diabetes.