Beclin-1 dependent autophagy improves renal outcomes following Unilateral Ureteral Obstruction (UUO) injury.
Beclin-1 dependent autophagy improves renal outcomes following Unilateral Ureteral Obstruction (UUO) injury.
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DOI：
10.3389/fimmu.2023.1104652
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发表时间：
2023
影响因子：
7.3
通讯作者：
Zang, Qun Sophia
中科院分区：
文献类型：
--
作者：
Lopez-Soler, Reynold I. I.;Nikouee, Azadeh;Kim, Matthew;Khan, Saman;Sivaraman, Lakshmi;Ding, Xiangzhong;Zang, Qun Sophia
间质纤维化和肾小管萎缩(IFTA)是肾移植后长期移植失败的最常见原因。IFTA的特征之一是间质纤维化的发展和正常肾脏结构的丧失。在这项研究中，我们评估了自噬启动因子Beclin-1在预防肾损伤后纤维化中的作用。成年雄性野生型(WT)C57BL/6小鼠造成单侧输尿管梗阻(UUO)，分别于伤后72小时、1周和3周取肾组织标本。对UUO损伤和未损伤的肾脏样本进行组织学检查，以了解纤维化、自噬流量、炎症以及综合应激反应(ISR)的激活情况。我们比较了WT小鼠和强制表达构成活性突变形式Beclin-1的小鼠，Becn1F121A/F121A。在所有实验中，UUO损伤导致纤维化和炎症的进行性发展。这些病理征象在Becn1F121a/F121a小鼠中明显减弱。在WT动物中，UUO引起自噬通量的强烈阻断，表现为损伤后1周Lc3II持续增加，并伴有超过3倍的p62积聚。然而，在Becn1F121a/F121a小鼠中，观察到UUO增加了Lc3II和未受影响的p62水平，这表明破坏的自噬得到了缓解。BECLIN-1F121a突变使炎症刺痛信号的磷酸化水平显著降低，IL-6和干扰素γ的产生受到限制，但对肿瘤坏死因子-α的影响不明显。此外，在UUO损伤的肾脏中，除了ISR效应分子ATF4的刺激表达外，还检测到ISR信号级联激活，即elF2S1和perk的磷酸化信号。然而，Becn1F121A/F121A小鼠在相同的条件下没有表现出elF2S1和PERK激活的迹象，并且在损伤后3周ATF水平显著降低。结果提示，UUO导致肾脏自噬功能不足、适应性不良，从而触发炎症刺痛通路的下游激活、细胞因子的产生和ISR的病理激活，最终导致纤维化的发展。通过对炎症介质的不同调控和控制不适应的ISR的潜在机制，通过Beclin-1增强自噬可以改善肾脏预后，减少纤维化。
Interstitial Fibrosis and Tubular Atrophy (IFTA) is the most common cause of long-term graft failure following renal transplant. One of the hallmarks of IFTA is the development of interstitial fibrosis and loss of normal renal architecture. In this study, we evaluated the role of autophagy initiation factor Beclin-1 in protecting against post-renal injury fibrosis. Adult male wild type (WT) C57BL/6 mice were subjected to Unilateral Ureteral Obstruction (UUO), and kidney tissue samples were harvested at 72-hour, 1- and 3-week post-injury. The UUO-injured and uninjured kidney samples were examined histologically for fibrosis, autophagy flux, inflammation as well activation of the Integrated Stress Response (ISR). We compared WT mice with mice carrying a forced expression of constitutively active mutant form of Beclin-1, Becn1F121A/F121A . In all experiments, UUO injury induces a progressive development of fibrosis and inflammation. These pathological signs were diminished in Becn1F121A/F121A mice. In WT animals, UUO caused a strong blockage of autophagy flux, indicated by continuously increases in LC3II accompanied by an over 3-fold accumulation of p62 1-week post injury. However, increases in LC3II and unaffected p62 level by UUO were observed in Becn1F121A/F121A mice, suggesting an alleviation of disrupted autophagy. Beclin-1 F121A mutation causes a significant decrease in phosphorylation of inflammatory STING signal and limited production of IL6 and IFNγ, but had little effect on TNF-α, in response to UUO. Furthermore, activation of ISR signal cascade was detected in UUO-injured in kidneys, namely the phosphorylation signals of elF2S1 and PERK in addition to the stimulated expression of ISR effector ATF4. However, Becn1F121A/F121A mice did not reveal signs of elF2S1 and PERK activation under the same condition and had a dramatically reduced ATF level at 3-week post injury. The results suggest that UUO causes a insufficient, maladaptive renal autophagy, which triggered downstream activation of inflammatory STING pathway, production of cytokines, and pathological activation of ISR, eventually leading to the development of fibrosis. Enhancing autophagy via Beclin-1 improved renal outcomes with diminished fibrosis, via underlying mechanisms of differential regulation of inflammatory mediators and control of maladaptive ISR.
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影响因子：
5.4
作者：
Kim, Matthew;Nikouee, Azadeh;Zou, Raymond;Ren, Di;He, Zhibin;Li, Ji;Wang, Lu;Djukovic, Danijel;Raftery, Daniel;Purcell, Hayley;Promislow, Daniel;Sun, Yuxiao;Goodarzi, Mohammad;Zhang, Qing-Jun;Liu, Zhi-Ping;Zang, Qun Sophia
通讯作者：
Zang, Qun Sophia
影响因子：
5.6
作者：
Fu, Ying;Xiang, Yu;Wu, Wenwen;Cai, Juan;Tang, Chengyuan;Dong, Zheng
通讯作者：
Dong, Zheng
影响因子：
9
作者：
Liu Z;Lv Y;Zhao N;Guan G;Wang J
通讯作者：
Wang J
影响因子：
--
作者：
Hartig, Sean M
通讯作者：
Hartig, Sean M
影响因子：
2.5
作者：
Kim, Wan-Young;Nam, Sun Ah;Kim, Yong Kyun
通讯作者：
Kim, Yong Kyun