Department of Nephrology, Sir Run Hospital, Nanjing Medical University, Jiangsu, China Nanjing.
Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Jiangsu, China Nanjing.
Ren Fail. 2023 Dec;45(1):2188966. doi: 10.1080/0886022X.2023.2188966.
Renal dysfunction and disruption of renal endothelial glycocalyx are two important events during septic acute kidney injury (AKI). Here, the role and mechanism of hyaluronidase 1 (HYAL1) in regulating renal injury and renal endothelial glycocalyx breakdown in septic AKI were explored for the first time.
BALB/c mice were injected with lipopolysaccharide (LPS, 10 mg/kg) to induce AKI. HYAL1 was blocked using lentivirus-mediated short hairpin RNA targeting HYAL1 (LV-sh-HYAL1). Biochemical assays were performed to measure the levels and concentrations of biochemical parameters associated with AKI as well as levels of inflammatory cytokines. Renal pathological lesions were determined by hematoxylin-eosin (HE) staining. Cell apoptosis in the kidney was detected using terminal-deoxynucleoitidyl transferase-mediated nick end labeling (TUNEL) assay. Immunofluorescence and immunohistochemical (IHC) staining assays were used to examine the levels of hyaluronic acid in the kidney. The protein levels of adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, endothelial glycocalyx, and autophagy-associated indicators were assessed by western blotting.
The knockdown of HYAL1 in LPS-subjected mice by LV-sh-HYAL1 significantly reduced renal inflammation, oxidative stress, apoptosis and kidney dysfunction in AKI, as well as alleviated renal endothelial glycocalyx disruption by preventing the release of hyaluronic acid to the bloodstream. Additionally, autophagy-related protein analysis indicated that knockdown of HYAL1 significantly enhanced autophagy in LPS mice. Furthermore, the beneficial actions of HYAL1 blockade were closely associated with the AMPK/mTOR signaling.
HYAL1 deficiency attenuates LPS-triggered renal injury and endothelial glycocalyx breakdown in septic AKI in mice.
肾功能障碍和肾脏内皮糖萼破坏是脓毒症急性肾损伤（AKI）的两个重要事件。在这里，我们首次探讨了透明质酸酶 1（HYAL1）在调节脓毒症 AKI 中肾脏损伤和肾脏内皮糖萼破坏中的作用和机制。
用脂多糖（LPS，10mg/kg）注射 BALB/c 小鼠以诱导 AKI。使用靶向 HYAL1 的慢病毒介导短发夹 RNA（LV-sh-HYAL1）阻断 HYAL1。通过生化测定来测量与 AKI 相关的生化参数的水平和浓度以及炎症细胞因子的水平。通过苏木精-伊红（HE）染色来确定肾脏的病理损伤。通过末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）检测来检测肾脏中的细胞凋亡。免疫荧光和免疫组织化学（IHC）染色检测肾脏中透明质酸的水平。通过 Western blot 评估 AMPK/mTOR 信号、内皮糖萼和自噬相关指标的蛋白水平。
用 LV-sh-HYAL1 敲低 LPS 处理的小鼠中的 HYAL1 显著减轻了 AKI 中的肾脏炎症、氧化应激、细胞凋亡和肾功能障碍，并通过防止透明质酸释放到血液中来减轻肾脏内皮糖萼的破坏。此外，自噬相关蛋白分析表明，HYAL1 敲低显著增强了 LPS 小鼠中的自噬。此外，HYAL1 阻断的有益作用与 AMPK/mTOR 信号密切相关。
HYAL1 缺乏可减轻 LPS 诱导的脓毒症 AKI 小鼠的肾脏损伤和内皮糖萼破坏。
