Department of Nephropathy, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, China.
Chin J Physiol. 2023 Mar-Apr;66(2):73-84. doi: 10.4103/cjop.CJOP-D-22-00122.
Acute kidney injury (AKI) is one of the most challenging clinical problems in kidney disease due to serious complications and high mortality rate, which can lead to acute lung injury (ALI) through inflammatory reactions and oxidative stress. Adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway has been reported to be involved in the development of renal ischemia-reperfusion through autophagy and it remains unclear whether AMPK/mTOR pathway has an effect on the AKI-induced ALI. In this study, we aimed to investigate the effects of autophagy-related AMPK/mTOR signaling pathway on inflammatory factors and oxidative stress in an AKI-induced ALI model. The 48 male Sprague-Dawley rats were divided into four groups randomly: (i) sham, (ii) ischemia/reperfusion injury (IRI), (iii) IRI + rapamycin (RA), and (iv) IRI + 3-methyladenine (3-MA). Unilateral flank incisions were made and right kidneys were excised. The left kidney was subjected to 60 min of ischemia followed by 12, 24, 48, and 72 h of reperfusion. The levels of Scr, blood urea nitrogen (BUN), Wet/Dry ratio, indexes of inflammation, and oxidative stress were assayed. Histological examinations were performed. The protein expression of AMPK, mTOR, LC3-II/LC3-I ratio, and Beclin-1, ULK1 was evaluated by western blotting and immunohistochemistry. Compared to the rats from the sham group, IRI rats showed significantly pulmonary damage after AKI with increased Scr, BUN, Wet/Dry ratio, indexes of inflammation, and oxidative stress. The expression of AMPK, LC3-II/LC3-I ratio, Beclin-1, and ULK1 and were increased, while p62 and mTOR were decreased. In addition, RA treatment significantly attenuated lung injury by promoting autophagy through the activation of the AMPK/mTOR pathway, and 3-MA treatment exhibited adverse effects inversely. Therefore, the activation of the AMPK/mTOR pathway after renal IRI induction could significantly attenuate kidney injury and following AKI-induced ALI by inducing autophagy, which alienates inflammation, oxidative stress, and apoptosis.
急性肾损伤（AKI）是肾脏疾病中最具挑战性的临床问题之一，因为它会导致严重的并发症和高死亡率，并且通过炎症反应和氧化应激可导致急性肺损伤（ALI）。已报道腺苷单磷酸激活蛋白激酶（AMPK）/雷帕霉素靶蛋白（mTOR）通路通过自噬参与肾缺血再灌注的发展，但 AMPK/mTOR 通路是否对 AKI 诱导的 ALI 有影响尚不清楚。在这项研究中，我们旨在研究自噬相关的 AMPK/mTOR 信号通路对 AKI 诱导的 ALI 模型中炎症因子和氧化应激的影响。将 48 只雄性 Sprague-Dawley 大鼠随机分为四组：（i）假手术组，（ii）缺血再灌注损伤（IRI）组，（iii）IRI+雷帕霉素（RA）组和（iv）IRI+3-甲基腺嘌呤（3-MA）组。进行单侧侧腹部切口并切除右肾。左肾进行 60 分钟的缺血，然后再灌注 12、24、48 和 72 小时。测定 Scr、血尿素氮（BUN）、湿重/干重比、炎症和氧化应激指标。进行组织学检查。通过 Western 印迹和免疫组织化学法评估 AMPK、mTOR、LC3-II/LC3-I 比值和 Beclin-1、ULK1 的蛋白表达。与 sham 组大鼠相比，AKI 后 IRI 大鼠的肺部损伤明显，Scr、BUN、湿重/干重比、炎症和氧化应激指标均升高。AMPK、LC3-II/LC3-I 比值、Beclin-1 和 ULK1 的表达增加，而 p62 和 mTOR 的表达减少。此外，通过激活 AMPK/mTOR 通路促进自噬，RA 治疗可显著减轻肺损伤，而 3-MA 治疗则产生相反的不利影响。因此，肾 IRI 诱导后 AMPK/mTOR 通路的激活可通过诱导自噬显著减轻肾损伤和随后的 AKI 诱导的 ALI，从而阻断炎症、氧化应激和细胞凋亡。
