College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
College of Animal Science and Technology, Jilin Agricultural Science and Technology University, Jilin, China.
Mol Med. 2024 Oct 25;30(1):184. doi: 10.1186/s10020-024-00964-y.
Sepsis-associated acute kidney injury (AKI) is a serious complication of systemic infection with high morbidity and mortality in patients. However, no effective drugs are available for AKI treatment. Dexmedetomidine (DEX) is an alpha 2 adrenal receptor agonist with antioxidant and anti-apoptotic effects. This study aimed to investigate the therapeutic effects of DEX on sepsis-associated AKI and to elucidate the role of mitochondrial dynamics during this process.
A lipopolysaccharide (LPS)-induced AKI rat model and an NRK-52E cell model were used in the study. This study investigated the effects of DEX on sepsis-associated AKI and the molecular mechanisms using histologic assessment, biochemical analyses, ultrastructural observation, western blotting, immunofluorescence, immunohistochemistry, qRT-PCR, flow cytometry, and si-mRNA transfection.
In rats, the results showed that administration of DEX protected kidney structure and function from LPS-induced septic AKI. In addition, we found that DEX upregulated the α2-AR/SIRT1/PGC-1α pathway, protected mitochondrial structure and function, and decreased oxidative stress and apoptosis compared to the LPS group. In NRK-52E cells, DEX regulated the mitochondrial dynamic balance by preventing intracellular Ca overloading and activating CaMKII.
DEX ameliorated septic AKI by reducing oxidative stress and apoptosis in addition to modulating mitochondrial dynamics via upregulation of the α2-AR/SIRT1/PGC-1α pathway. This is a confirmatory study about DEX pre-treatment to ameliorate septic AKI. Our research reveals a novel mechanistic molecular pathway by which DEX provides nephroprotection.
脓毒症相关性急性肾损伤（AKI）是全身感染的严重并发症，患者发病率和死亡率高。然而，目前尚无有效的 AKI 治疗药物。右美托咪定（DEX）是一种α2肾上腺受体激动剂，具有抗氧化和抗细胞凋亡作用。本研究旨在探讨 DEX 对脓毒症相关性 AKI 的治疗作用，并阐明其在这一过程中线粒体动力学的作用。
本研究采用脂多糖（LPS）诱导的 AKI 大鼠模型和 NRK-52E 细胞模型，通过组织学评估、生化分析、超微结构观察、Western blot、免疫荧光、免疫组化、qRT-PCR、流式细胞术和 si-mRNA 转染等方法，研究 DEX 对脓毒症相关性 AKI 的影响及其分子机制。
在大鼠中，DEX 可保护 LPS 诱导的脓毒症 AKI 大鼠的肾脏结构和功能。此外，我们发现 DEX 可通过上调α2-AR/SIRT1/PGC-1α 通路，保护线粒体结构和功能，减少氧化应激和细胞凋亡，与 LPS 组相比，效果更好。在 NRK-52E 细胞中，DEX 通过防止细胞内 Ca2+超载和激活 CaMKII 来调节线粒体动力学平衡。
DEX 通过上调α2-AR/SIRT1/PGC-1α 通路减轻氧化应激和细胞凋亡，从而改善脓毒症相关性 AKI，此外，还通过调节线粒体动力学。这是一项关于 DEX 预处理以改善脓毒症相关性 AKI 的验证性研究。我们的研究揭示了 DEX 提供肾脏保护的一种新的机制分子途径。
