MiR-181d-5p Targets KLF6 to Improve Ischemia/Reperfusion-Induced AKI Through Effects on Renal Function, Apoptosis, and Inflammation
Yue Zhang, Chenyu Li, Guan Chen, Bin Zhou, Lin Wang, Chengyu Yang, Zhen Li, Jie Dai, Long Zhao, Wei Jiang, Yan Xu
Abstract
Renal tubular epithelial cell (RTEC) death and renal interstitial inflammation are the most crucial pathophysiological changes in acute kidney ischemia/reperfusion injury (IRI). The microRNA (miR)-181d family plays diverse roles in cell proliferation, apoptosis and inflammation, but its renal target and potential role in IRI are unknown. Here, we showed that the expression of miR-181d-5p decreased in a renal cell (HK-2) model of hypoxia/reoxygenation (H/R) injury and a mouse model of renal IRI. Mechanistically, KLF6 was predicted as a new potential target gene of miR-181d-5p through bioinformatic analysis and luciferase reporter assay verification. After renal I/R, overexpression of miR-181d-5p significantly attenuated the level of KLF6 and inhibited inflammatory mediators, reducing apoptosis and further improving renal function. Pivotal NF-κB signaling pathways regulated the inflammatory response. In conclusion, miR-181d-5p upregulation produced protective antiapoptotic and anti-inflammatory effects against IRI in kidneys in vivo and H/R injury in HK-2 cells in vitro, and these effects were achieved by targeted inhibition of KLF6. Thus, our results provide novel insights into the molecular mechanisms associated with IRI and a potential novel therapeutic target.