Lou Yunpeng, Shi Hongguang, Sha Ning, Li Feifei, Gu Xiaofeng, Lin Huiyan
Department of Intensive Care Medicine, No. 971st Hospital of the People's Liberation Army Navy, Qingdao, Shandong Province, PR China.
Department of Nephrology, No. 971st Hospital of the People's Liberation Army Navy, Qingdao, Shandong Province, PR China.
BMC Nephrol. 2025 Jan 30;26(1):45. doi: 10.1186/s12882-025-03977-9.
Ursodeoxycholic acid (UDCA), traditionally recognized for its hepatoprotective effects, has also shown potential in protecting kidney injury. This study aimed to evaluate the protective effects of UDCA against sepsis-induced acute kidney injury (AKI) and to elucidate the underlying mechanisms.
Sixty male C57BL/6 N mice were utilized to establish a sepsis-induced AKI model through intravenous injection of lipopolysaccharides (LPS, 10 mg/kg). UDCA (15, 30, and 60 mg/kg) was administered intraperitoneally once daily for 7 days before LPS injection. Kidney injury was evaluated by HE staining and biochemical markers, including serum creatinine (Cr), blood urea nitrogen (BUN), urinary protein, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and retinol binding protein (RBP). Oxidative stress parameters and nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) pathway, pro-inflammatory cytokines and nuclear factor-kappa B (NF-κB) pathway were also evaluated. Additionally, HK-2 cells were treated with LPS in vitro, and cell viability and apoptosis were detected using CCK-8 kit and flow cytometer, respectively.
UDCA significantly attenuated LPS-induced renal histopathological damage and improved renal function, as evidenced by reduction in serum Cr, BUN, and urinary protein levels. UDCA also up-regulated the protein expression of zonula occludens-1 (ZO-1) and Ezrin in the kidney, and reduced the urinary levels of NGAL, KIM-1, NAG, and RBP. Moreover, UDCA inhibited NF-κB p65 phosphorylation and reduced pro-inflammatory cytokines levels (TNF-α, IL-1β, and IL-6) in both serum and kidney. UDCA alleviated oxidative stress by activating the Nrf2/HO-1 pathway in the kidney. In vitro, UDCA reduced LPS-induced cell injury and apoptosis in HK-2 cells, with these protective effects being blocked by the Nrf2 inhibitor ML385.
Our present study demonstrated that UDCA exerts protective effects against sepsis-induced AKI by attenuating oxidative stress and inflammation, primarily through the activation of the Nrf2/HO-1 pathway and inhibition of the NF-κB pathway. These findings highlight the therapeutic potential of UDCA in preventing sepsis-induced AKI.
熊去氧胆酸（UDCA）传统上因其肝脏保护作用而被认可，在保护肾脏损伤方面也显示出潜力。本研究旨在评估UDCA对脓毒症诱导的急性肾损伤（AKI）的保护作用，并阐明其潜在机制。
60只雄性C57BL/6 N小鼠通过静脉注射脂多糖（LPS，10 mg/kg）建立脓毒症诱导的AKI模型。在注射LPS前7天，每天腹腔注射一次UDCA（15、30和60 mg/kg）。通过HE染色和生化指标评估肾脏损伤，生化指标包括血清肌酐（Cr）、血尿素氮（BUN）、尿蛋白、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、肾损伤分子-1（KIM-1）、N-乙酰-β-D-氨基葡萄糖苷酶（NAG）和视黄醇结合蛋白（RBP）。还评估了氧化应激参数以及核因子红细胞2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）途径、促炎细胞因子和核因子-κB（NF-κB）途径。此外，体外使用LPS处理HK-2细胞，并分别使用CCK-8试剂盒和流式细胞仪检测细胞活力和凋亡情况。
UDCA显著减轻LPS诱导的肾脏组织病理学损伤并改善肾功能，血清Cr、BUN和尿蛋白水平降低证明了这一点。UDCA还上调了肾脏中紧密连接蛋白-1（ZO-1）和埃兹蛋白的蛋白表达，并降低了尿中NGAL、KIM-1、NAG和RBP的水平。此外，UDCA抑制NF-κB p65磷酸化，并降低血清和肾脏中促炎细胞因子水平（TNF-α、IL-1β和IL-6）。UDCA通过激活肾脏中的Nrf2/HO-1途径减轻氧化应激。在体外，UDCA减少了LPS诱导的HK-2细胞损伤和凋亡，Nrf2抑制剂ML385阻断了这些保护作用。
我们目前的研究表明，UDCA通过减轻氧化应激和炎症对脓毒症诱导的AKI发挥保护作用，主要是通过激活Nrf2/HO-1途径和抑制NF-κB途径。这些发现突出了UDCA在预防脓毒症诱导的AKI方面的治疗潜力。
