Alteration in microRNA-25 Balance Causes Heart and Kidney Impairment. Mus musculus

Contradictorily, both up- and downregulation of miR-25 can reverse heart failure. Importantly, these findings were based on the same animal model of pressure overloaded transverse aortic constriction (TAC) mice. How can we explain and, if possible, reconcile these two conflicting findings? Heart failure is a multi-step process that involves multiple organs, and we hypothesized that determining whether altering miR-25 alone could induce heart failure should provide a mechanistic basis for miR-25’s action in this process. Here, we show that overexpression of miR-25 in normal mice caused cardiomyocyte fibrosis and apoptosis but no obvious kidney impairment. By contrast, inhibition of miR-25 in normal mice led to hypertension, mild heart dilation, and severe kidney dysfunction. With the expectation that restoring miR-25 might ameliorate kidney injury, we demonstrated that increasing miR-25 reversed proteinuria and kidney fibrosis in diabetic nephropathy. MiR-25 expression in humans is initially decreased at the onset of heart failure but is later increased in end-stage heart failure. RNA sequencing of mouse kidneys with elevated and reduced miR-25 identified distinct alterations of a number of putative miR-25 target mRNAs, including those involved in the Ras signaling pathway, oxidant stress. In summary, differences in miR-25 expression during different stages of heart disease and its distinct roles in the heart and kidney, offer a new perspective for the role of miR-25 function in heart failure, which may begin to resolve this catch-22. Overall design: Detect the mRNA alteration in wildtype and miR-25 agomir or antagomir treated mice

令人矛盾的是，微小RNA-25（miR-25）的上调与下调均可逆转心力衰竭。值得注意的是，上述两项研究结论均基于同一压力负荷过载型横主动脉缩窄术（transverse aortic constriction, TAC）小鼠动物模型。我们该如何解释这一现象，若有可能，又该如何调和这两项相互矛盾的研究结果？心力衰竭是一个涉及多器官的多步骤病理过程，我们推测，明确单独调控miR-25是否可诱发心力衰竭，将为阐明miR-25在该过程中的作用机制提供依据。
本研究证实，在正常小鼠体内过表达miR-25会引发心肌纤维化与心肌细胞凋亡，但未出现明显的肾脏损伤。与之相反，在正常小鼠中抑制miR-25则会导致高血压、轻度心脏扩张以及严重的肾功能障碍。鉴于恢复miR-25表达或可减轻肾脏损伤，我们进一步证实，提升miR-25水平可逆转糖尿病肾病中的蛋白尿与肾脏纤维化。
人类体内的miR-25表达在心力衰竭发病初期呈下调趋势，但在终末期心力衰竭阶段则会上调。对miR-25表达水平升高与降低的小鼠肾脏进行RNA测序（RNA sequencing）后发现，大量推定的miR-25靶信使RNA（mRNA）发生了显著表达改变，其中包括参与Ras信号通路、氧化应激相关的靶基因。
总而言之，miR-25在心脏疾病不同阶段的表达差异，及其在心脏与肾脏中发挥的截然不同的作用，为阐明miR-25在心力衰竭中的功能提供了全新视角，或有望解决这一进退两难的研究困境。
实验整体设计：检测野生型小鼠以及经miR-25激动剂（agomir）或拮抗剂（antagomir）处理的小鼠体内的mRNA表达变化。