Prior studies have established the important role of extracellular signal-regulated kinase 1/2 (ERK1/2) as a mediator of acute kidney injury (AKI). We demonstrated rapid ERK1/2 activation induced renal dysfunction following ischemia/reperfusion (IR)-induced AKI and downregulated the mitochondrial biogenesis (MB) regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in mice. In this study, ERK1/2 regulation of cellular nicotinamide adenine dinucleotide (NAD) and PGC-1α were explored. Inhibition of ERK1/2 activation during AKI in mice using the MEK1/2 inhibitor, trametinib, attenuated renal cortical oxidized NAD (NAD⁺) depletion. The rate-limiting NAD biosynthesis salvage enzyme, NAMPT, decreased following AKI, and this decrease was prevented by ERK1/2 inhibition. The microRNA miR34a decreased with the inhibition of ERK1/2, leading to increased NAMPT protein. Mice treated with a miR34a mimic prevented increases in NAMPT protein in the renal cortex in the presence of ERK1/2 inhibition. In addition, ERK1/2 activation increased acetylated PGC-1α, the less active form, whereas inhibition of ERK1/2 activation prevented an increase in acetylated PGC-1α after AKI through SIRT1 and NAD⁺ attenuation. These results implicate IR-induced ERK1/2 activation as an important contributor to the downregulation of both PGC-1α and NAD⁺ pathways that ultimately decrease cellular metabolism and renal function. Inhibition of ERK1/2 activation prior to the initiation of IR injury attenuated decreases in PGC-1α and NAD⁺ and prevented kidney dysfunction.

先前的研究已经确定了细胞外信号调节激酶1/2（ERK1 / 2）作为急性肾损伤（AKI）的介质的重要作用。我们证明了小鼠缺血/再灌注（IR）引起的AKI后快速ERK1 / 2激活引起的肾功能不全，并下调了小鼠的线粒体生物发生（MB）调节剂，过氧化物酶体增殖物激活受体γcoactivator-1α（PGC-1α）。在这项研究中，探索了细胞烟酰胺腺嘌呤二核苷酸（NAD）和PGC-1α的ERK1 / 2调控。使用MEK1 / 2抑制剂曲美替尼，减弱的肾皮质氧化NAD（NAD ⁺）耗竭。限速NAD生物合成挽救酶NAMPT在AKI后降低，并且这种降低被ERK1 / 2抑制所阻止。microRNA miR34a随着ERK1 / 2的抑制而降低，导致NAMPT蛋白增加。在ERK1 / 2抑制作用下，用miR34a模拟物治疗的小鼠阻止了肾皮质NAMPT蛋白的增加。此外，ERK1 / 2激活增加了活性较低的乙酰化PGC-1α，而抑制ERK1 / 2激活阻止了AKI通过SIRT1和NAD ⁺衰减后乙酰化PGC-1α的增加。这些结果暗示IR诱导的ERK1 / 2激活是PGC-1α和NAD ⁺下调的重要因素。最终降低细胞代谢和肾功能的途径。在IR损伤开始之前抑制ERK1 / 2激活减弱了PGC-1α和NAD ^+的减少，并预防了肾功能不全。