Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia.
Am J Physiol Renal Physiol. 2020 Apr 1;318(4):F878-F887. doi: 10.1152/ajprenal.00567.2019. Epub 2020 Jan 31.
Disruption of mitochondrial dynamics is an important pathogenic event in both acute and chronic kidney diseases, but the underlying mechanism remains poorly understood. Here, we report the regulation of mitofusin-2 (Mfn2; a key mitochondrial fusion protein) by microRNA-214 (miR-214) in renal ischemia-reperfusion that contributes to mitochondrial fragmentation, renal tubular cell death, and ischemic acute kidney injury (AKI). miR-214 was induced, whereas Mfn2 expression was decreased, in mouse ischemic AKI and cultured rat kidney proximal tubular cells (RPTCs) following ATP depletion treatment. Overexpression of miR-214 decreased Mfn2. Conversely, inhibition of miR-214 with anti-miR-214 prevented Mfn2 downregulation in RPTCs following ATP depletion. Anti-miR-214 further ameliorated mitochondrial fragmentation and apoptosis, whereas overexpression of miR-214 increased apoptosis, in ATP-depleted RPTCs. To test regulation in vivo, we established a mouse model with miR-214 specifically deleted from kidney proximal tubular cells (PT-). Compared with wild-type mice, PT- mice had less severe tissue damage, fewer apoptotic cells, and better renal function after ischemic AKI. miR-214 induction in ischemic AKI was suppressed in PT- mice, accompanied by partial preservation of Mfn2 in kidneys. These results unveil the miR-214/Mfn2 axis that contributes to the disruption of mitochondrial dynamics and tubular cell death in ischemic AKI, offering new therapeutic targets.
线粒体动力学的破坏是急性和慢性肾脏病的重要发病事件，但潜在机制仍知之甚少。在这里，我们报告了 microRNA-214（miR-214）对肾缺血再灌注中线粒体融合蛋白-2（Mfn2）的调节，该调节导致线粒体碎片化、肾小管细胞死亡和缺血性急性肾损伤（AKI）。在小鼠缺血性 AKI 和培养的大鼠肾近端肾小管细胞（RPTC）中，miR-214 在 ATP 耗竭处理后被诱导，而 Mfn2 的表达则减少。miR-214 的过表达降低了 Mfn2。相反，在 ATP 耗竭的 RPTC 中，用抗 miR-214 抑制 miR-214 可防止 Mfn2 的下调。抗 miR-214 进一步改善了 ATP 耗竭的 RPTC 中的线粒体碎片化和凋亡，而 miR-214 的过表达增加了凋亡。为了在体内进行测试，我们建立了一种肾脏近端肾小管细胞（PT-）特异性缺失 miR-214 的小鼠模型。与野生型小鼠相比，PT-小鼠在缺血性 AKI 后组织损伤较轻，凋亡细胞较少，肾功能较好。在 PT-小鼠中，缺血性 AKI 中 miR-214 的诱导被抑制，同时肾脏中 Mfn2 部分保留。这些结果揭示了 miR-214/Mfn2 轴在缺血性 AKI 中线粒体动力学破坏和管状细胞死亡中的作用，为新的治疗靶点提供了依据。
