miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-α activation
miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-α activation
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DOI：
10.1152/ajprenal.00287.2012
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发表时间：
2013-05-01
影响因子：
4.2
通讯作者：
Ding, Xiaoqiang
中科院分区：
文献类型：
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作者：
Fang, Yi;Yu, Xiaofang;Ding, Xiaoqiang
L可激活低氧诱导因子-α，减轻大鼠残肾模型肾小管间质损伤，改善肾功能。MiR-29家族的microRNAs直接靶向大量的细胞外基质基因，减少肾间质纤维化。我们分析了L含羞草处理前后大鼠残肾组织中的microRNA表达谱。与假手术对照组相比，大鼠残肾中miR-29c的表达下调，经L-含草素治疗后，miR-29c的表达明显恢复。在培养的人肾上皮HK2细胞中，氯化钴激活了HIF-α，上调了miR-29c的表达。抑制HIF-1α或HIF-2α可显著降低miR-29c的表达。在大鼠残肾和IgA肾病患者的肾脏中，miR-29c表达下调与间质纤维化、II型胶原α1(COL2A1)蛋白和原肌球蛋白1α(TPM1)蛋白显著增加相关。L-米莫辛治疗可减轻大鼠残肾重量的增加。COL2A1和TPM1被确认为miR-29c的新的直接靶点。综上所述，miR-29c，一种抗纤维化的microRNA，被HIF-α激活上调。在人和大鼠的肾间质纤维化中，MIR-29c表达下调，并通过激活HIF-α来恢复，从而减轻纤维化。
Treatment with L-mimosine, which activates hypoxia-inducible factor-alpha (HIF-alpha), attenuates renal tubulointerstitial injury and improves renal function in a rat remnant kidney model. The miR-29 family of microRNAs directly targets a large number of extracellular matrix genes and reduces renal interstitial fibrosis. We analyzed microRNA expression profiles in rat remnant kidneys with or without treatment with L-mimosine. The expression of miR-29c was downregulated in rat remnant kidneys compared with sham control and significantly restored by the L-mimosine treatment. In cultured human kidney epithelial HK2 cells, cobalt chloride activated HIF-alpha and upregulated miR-29c expression. The upregulation of miR-29c expression was significantly attenuated by knockdown of HIF-1 alpha or HIF-2 alpha. Downregulation of miR-29c was associated with significant increases in interstitial fibrosis, collagen type II alpha 1 (COL2A1) protein, and tropomyosin 1 alpha (TPM1) protein in rat remnant kidneys and in kidneys from IgA nephropathy patients. The increases in rat remnant kidneys were attenuated by the L-mimosine treatment. COL2A1 and TPM1 were confirmed to be new, direct targets of miR-29c. In conclusion, miR-29c, an antifibrotic microRNA, is upregulated by HIF-alpha activation. MiR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by activation of HIF-alpha that attenuates fibrosis.