Zhang Jie, Li Kun-Yuan, Liu Xiao-You, Tu Yan-Yang
Department of Organ Transplantation, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China.
Department of Organ Transplantation, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China.
Free Radic Biol Med. 2021 Nov 29. doi: 10.1016/j.freeradbiomed.2021.11.035.
Prolonged cold ischemia (CI) is a risk factor for acute kidney injury (AKI) after kidney transplantation (KT). AKI is an abrupt and rapid reduction in renal function due to multi-factors, including inflammation, oxidative stress and apoptosis. V-set immunoglobulin-domain-containing 4 (VSIG4) is a B7 family-related protein and specifically expressed in resting tissue-resident macrophages to mediate various cellular events. In the study, we attempted to explore the effects of VSIG4 on CI/KT-induced AKI in a mouse model. Our results showed that VSIG4 expression was markedly down-regulated in serum of kidney transplant recipients with acute rejection, and in renal tissues of cold ischemia-reperfusion (IR)-operated mice with AKI, which was confirmed in murine macrophages stimulated by oxygen glucose deprivation/reoxygenation (OGD/R). We then found that exogenous VSIG4 markedly ameliorated histological changes in kidney of CI/KT mice by suppressing inflammation and apoptosis through restraining nuclear factor-κB (NF-κB) and Caspase-3 activation, respectively. Oxidative stress and reactive oxygen species (ROS) accumulation in renal tissues were also mitigated by exogenous VSIG4 in CI/KT mice through improving nuclear factor-erythroid 2 related factor 2 (Nrf2) nuclear expression. The inhibitory effects of VSIG4 on inflammation, ROS generation and cell death were confirmed in OGD/R-treated macrophages, which further ameliorated oxidative damage and apoptosis in podocytes. More in vivo and in vitro studies showed that CI/KT- and OGD/R-induced AKI was further accelerated by VSIG4 knockdown. Mechanistically, VSIG4 directly interacted with AKT, and AKT activation was necessary for VSIG4 to govern all these above mentioned cellular processes. Collectively, our findings demonstrated that VSIG4 could mitigate AKI in a CI/KT mouse model, and we identified VSIG4/AKT axis as a promising therapeutic target for the treatment of the disease.
长时间冷缺血（CI）是肾移植（KT）后急性肾损伤（AKI）的一个危险因素。AKI是由于多种因素（包括炎症、氧化应激和细胞凋亡）导致的肾功能突然且快速下降。含V-set免疫球蛋白结构域4（VSIG4）是一种与B7家族相关的蛋白，在静止的组织驻留巨噬细胞中特异性表达，以介导各种细胞事件。在本研究中，我们试图在小鼠模型中探究VSIG4对CI/KT诱导的AKI的影响。我们的结果显示，急性排斥反应的肾移植受者血清中以及发生AKI的冷缺血-再灌注（IR）手术小鼠的肾组织中，VSIG4表达均显著下调，这在氧糖剥夺/复氧（OGD/R）刺激的小鼠巨噬细胞中得到证实。然后我们发现，外源性VSIG4通过分别抑制核因子-κB（NF-κB）和半胱天冬酶-3（Caspase-3）的激活来减轻炎症和细胞凋亡，从而显著改善CI/KT小鼠肾脏的组织学变化。外源性VSIG4还通过提高核因子红系2相关因子2（Nrf2）的核表达减轻了CI/KT小鼠肾组织中的氧化应激和活性氧（ROS）积累。VSIG4对炎症、ROS生成和细胞死亡的抑制作用在OGD/R处理的巨噬细胞中得到证实，这进一步改善了足细胞的氧化损伤和细胞凋亡。更多的体内和体外研究表明，VSIG4基因敲低会进一步加速CI/KT和OGD/R诱导的AKI。从机制上讲，VSIG4直接与AKT相互作用，并且AKT激活是VSIG4调控上述所有细胞过程所必需的。总的来说，我们的研究结果表明，VSIG4可以减轻CI/KT小鼠模型中的AKI，并且我们确定VSIG4/AKT轴是治疗该疾病的一个有前景的治疗靶点。
