Ban Ka-Yun, Nam Ga-Young, Kim Donghee, Oh Yoon Sin, Jun Hee-Sook
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea.
Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea.
Antioxidants (Basel). 2022 Oct 24;11(11):2096. doi: 10.3390/antiox11112096.
Acute kidney injury (AKI) is a serious complication of sepsis with a rapid onset and high mortality rate. Bavachin, an active component of L., reportedly has antioxidant, anti-apoptotic, and anti-inflammatory effects; however, its beneficial effects on AKI remain undetermined. We investigated the protective effect of bavachin on lipopolysaccharide (LPS)-induced AKI in mice and elucidated the underlying mechanism in human renal tubular epithelial HK-2 cells. Increased serum creatinine and blood urea nitrogen levels were observed in LPS-injected mice; however, bavachin pretreatment significantly inhibited this increase. Bavachin improved the kidney injury score and decreased the expression level of tubular injury markers, such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), in both LPS-injected mice and LPS-treated HK-2 cells. LPS-induced oxidative stress via phosphorylated protein kinase C (PKC) β and upregulation of the NADPH oxidase (NOX) 4 pathway was also significantly decreased by treatment with bavachin. Moreover, bavachin treatment inhibited the phosphorylation of MAPKs (P38, ERK, and JNK) and nuclear factor (NF)-κB, as well as the increase in inflammatory cytokine levels in LPS-injected mice. Krüppel-like factor 5 (KLF5) expression was upregulated in the LPS-treated HK-2 cells and kidneys of LPS-injected mice. However, RNAi-mediated silencing of KLF5 inhibited the phosphorylation of NF-kB, consequently reversing LPS-induced KIM-1 and NGAL expression in HK-2 cells. Therefore, bavachin may ameliorate LPS-induced AKI by inhibiting oxidative stress and inflammation via the downregulation of the PKCβ/MAPK/KLF5 axis.
急性肾损伤（AKI）是脓毒症的一种严重并发症，起病迅速，死亡率高。据报道，补骨脂二氢黄酮甲醚（bavachin）是补骨脂（Psoralea corylifolia L.）的一种活性成分，具有抗氧化、抗凋亡和抗炎作用；然而，其对AKI的有益作用尚未确定。我们研究了补骨脂二氢黄酮甲醚对脂多糖（LPS）诱导的小鼠急性肾损伤的保护作用，并阐明了其在人肾小管上皮HK-2细胞中的潜在机制。在注射LPS的小鼠中观察到血清肌酐和血尿素氮水平升高；然而，补骨脂二氢黄酮甲醚预处理显著抑制了这种升高。补骨脂二氢黄酮甲醚改善了肾损伤评分，并降低了注射LPS的小鼠和LPS处理的HK-2细胞中肾小管损伤标志物的表达水平，如中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和肾损伤分子-1（KIM-1）。补骨脂二氢黄酮甲醚处理还显著降低了LPS通过磷酸化蛋白激酶C（PKC）β诱导的氧化应激以及NADPH氧化酶（NOX）4途径的上调。此外，补骨脂二氢黄酮甲醚处理抑制了丝裂原活化蛋白激酶（MAPK）（P38、ERK和JNK）和核因子（NF）-κB的磷酸化，以及注射LPS的小鼠中炎性细胞因子水平的升高。在LPS处理的HK-2细胞和注射LPS的小鼠肾脏中，Krüppel样因子5（KLF5）表达上调。然而，RNA干扰介导的KLF5沉默抑制了NF-κB的磷酸化，从而逆转了LPS诱导的HK-2细胞中KIM-1和NGAL的表达。因此，补骨脂二氢黄酮甲醚可能通过下调PKCβ/MAPK/KLF5轴抑制氧化应激和炎症，从而改善LPS诱导的急性肾损伤。
