Nakamura Itaru, Umehara Minato, Yagi-Tomita Aya, Yamamoto Satomi, Sawai Shinji, Nakamura Masashi, Minamida Atsushi, Yamauchi-Sawada Hiroko, Sunahara Yasuto, Matoba Yayoi, Okuno-Ozeki Natsuko, Nakai Kunihiro, Nakata Tomohiro, Kitani Takashi, Yamashita Noriyuki, Komaki Kazumi, Kirita Yuhei, Tamagaki Keiichi, Matoba Satoaki, Kusaba Tetsuro
Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Sci Rep. 2025 Jul 1;15(1):22081. doi: 10.1038/s41598-025-05878-1.
Renal congestion is a key factor in renal dysfunction associated with heart failure. We previously reported that renal congestion worsened renal ischemia-reperfusion in a murine model. However, its impact on sepsis-associated acute kidney injury (SA-AKI), the leading cause of AKI, remains unclear. Therefore, we herein investigated the mechanisms by which renal congestion exacerbates SA-AKI, with a focus on Toll-like receptor (TLR) 2. After inducing sepsis with cecal ligation and puncture (CLP) in a unilateral renal congestion model, transient blood pressure reductions and persistent renal vein dilation were observed. A histological analysis showed increased fibrosis and its markers in congested kidneys post-CLP. Acute phase results revealed extensive tubular damage, macrophage infiltration, TLR2 up-regulation, and elevated high mobility group box 1 (HMGB1) levels. In TLR2-knockout mice, exacerbation of tissue fibrosis by renal congestion was attenuated after CLP. In vitro, oxidative stress and hypoxia up-regulated TLR2 expression. Collectively, these results suggest that renal congestion and sepsis synergistically worsened renal damage, likely through hypoxia and the oxidative stress-induced activation of the TLR2 pathway.
肾充血是与心力衰竭相关的肾功能障碍的关键因素。我们之前报道过，在小鼠模型中肾充血会加重肾缺血再灌注。然而，其对脓毒症相关性急性肾损伤（SA-AKI，急性肾损伤的主要原因）的影响仍不清楚。因此，我们在此研究肾充血加重SA-AKI的机制，重点关注Toll样受体（TLR）2。在单侧肾充血模型中通过盲肠结扎和穿刺（CLP）诱导脓毒症后，观察到短暂的血压降低和持续的肾静脉扩张。组织学分析显示CLP后充血肾脏中的纤维化及其标志物增加。急性期结果显示广泛的肾小管损伤、巨噬细胞浸润、TLR2上调以及高迁移率族蛋白B1（HMGB1）水平升高。在TLR2基因敲除小鼠中，CLP后肾充血对组织纤维化的加重作用减弱。在体外，氧化应激和缺氧会上调TLR2表达。总体而言，这些结果表明肾充血和脓毒症通过缺氧和氧化应激诱导的TLR2途径激活协同加重肾损伤。
