Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China.
Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China; Gansu Province Livestock Embryo Engineering Research Center, Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China.
Cell Signal. 2024 Dec;124:111450. doi: 10.1016/j.cellsig.2024.111450. Epub 2024 Oct 11.
Hypoxic environments are significant factors in the induction of various kidney diseases and are closely associated with high oxygen consumption in the kidneys. Yaks live at high altitude for a long time, exhibit a unique ability to regulate kidney oxygen consumption, protecting them from hypoxia-induced damage. However, the mechanisms underlying the regulation of oxygen consumption in yak kidneys under hypoxic conditions remain unclear. To explore this hypoxia adaptation mechanism in yak kidneys, this study analyzed the oxygen consumption rate (OCR) of renal tubular epithelial cells (RTECs) under hypoxia. We found that the OCR and apoptosis rates of RTECs under chronic hypoxia (> 24 h) were lower than those under acute hypoxia (≤ 24 h). However, when oxygen consumption was promoted under chronic hypoxia, the apoptosis rate increased, indicating that reducing the cellular OCR is crucial for maintaining RTECs activity under hypoxia. High-throughput sequencing results showed that the mitophagy pathway is likely a key mechanism for inhibiting OCR of yak RTECs, with protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) playing a significant role in this process. Further studies demonstrated that chronic hypoxia activates the mitophagy pathway, which inhibits oxidative phosphorylation (OXPHOS) while increasing glycolytic flux in yak RTECs. Conversely, when the mitophagy pathway was inhibited, there was an increase in the activity of OXPHOS enzymes and OCR. To further explore the role of PRKAA2 in the mitophagy pathway, we inhibited PRKAA2 expression under chronic hypoxia. Results showed that the downregulation of PRKAA2 decreased the expression of mitophagy-related proteins, such as p-FUNDC1/FUNDC1, LC3-II/LC3-I, BNIP3 and ULK1 while upregulating P62 expression. Additionally, there was an increase in the enzyme activities of Complex II, Complex IV, PDH, and SDH, which further promoted oxygen consumption in RTECs. These findings suggest that PRKAA2 mediated mitophagy under chronic hypoxia is crucial mechanism for reducing oxygen consumption in yak RTECs.
缺氧环境是诱发各种肾脏疾病的重要因素，与肾脏高耗氧量密切相关。牦牛长期生活在高海拔地区，具有独特的调节肾脏氧耗的能力，使其免受缺氧损伤。然而，牦牛肾脏在低氧条件下调节氧耗的机制尚不清楚。为了探讨牦牛肾脏的这种低氧适应机制，本研究分析了低氧条件下肾小管上皮细胞（RTEC）的耗氧率（OCR）。我们发现，慢性缺氧（>24 h）下 RTEC 的 OCR 和凋亡率低于急性缺氧（≤24 h）。然而，当慢性缺氧时促进氧消耗，凋亡率增加，表明降低细胞 OCR 对于维持 RTEC 在低氧下的活性至关重要。高通量测序结果表明，线粒体自噬途径可能是抑制牦牛 RTECs OCR 的关键机制，蛋白激酶 AMP 激活的催化亚基α2（PRKAA2）在这一过程中发挥重要作用。进一步研究表明，慢性缺氧激活了线粒体自噬途径，抑制了氧化磷酸化（OXPHOS），同时增加了牦牛 RTECs 的糖酵解通量。相反，当抑制线粒体自噬途径时，OXPHOS 酶和 OCR 的活性增加。为了进一步探讨 PRKAA2 在自噬途径中的作用，我们在慢性缺氧下抑制了 PRKAA2 的表达。结果表明，PRKAA2 下调降低了线粒体自噬相关蛋白的表达，如 p-FUNDC1/FUNDC1、LC3-II/LC3-I、BNIP3 和 ULK1，同时上调了 P62 的表达。此外，复合物 II、复合物 IV、PDH 和 SDH 的酶活性增加，进一步促进了 RTEC 中的氧消耗。这些发现表明，PRKAA2 介导的慢性缺氧下的线粒体自噬是减少牦牛 RTEC 氧耗的关键机制。
