The antioxidant and DNA-repair enzyme apurinic/apyrimidinic endonuclease 1 limits the development of tubulointerstitial fibrosis partly by modulating the immune system
The antioxidant and DNA-repair enzyme apurinic/apyrimidinic endonuclease 1 limits the development of tubulointerstitial fibrosis partly by modulating the immune system
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DOI：
10.1038/s41598-019-44241-z
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发表时间：
2019-05
影响因子：
4.6
通讯作者：
K. Maruyama;N. Nakagawa;Tatsuya Aonuma;Yukihiro Saito;Taiki Hayasaka;K. Kano;Kiwamu Horiuchi;N. Takehara;J. Kawabe;N. Hasebe
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作者：
K. Maruyama;N. Nakagawa;Tatsuya Aonuma;Yukihiro Saito;Taiki Hayasaka;K. Kano;Kiwamu Horiuchi;N. Takehara;J. Kawabe;N. Hasebe
无嘌呤/无嘧啶核酸内切酶 1 (APE1) 是一种多功能蛋白质，可控制细胞对氧化应激的反应并具有 DNA 修复功能。它在各种疾病的进展和结果中具有重要作用；然而，其在肾损伤方面的功能和治疗前景尚不清楚。为了研究这一点，我们通过构建表达载体 (pCAG-APE1) 在肾损伤期间激活 APE1，并使用 EGFP 表达质粒 (pCAG-EGFP) 作为对照。在通过逆行肾静脉注射给予每种载体之前，我们对 ICR 小鼠进行单侧输尿管梗阻（UUO）作为肾小管间质纤维化模型。在此模型中，与注射 pCAG-EGFP 后的参数相比，注射 pCAG-APE1 没有产生任何副作用，并且显着降低了组织学终点，包括纤维化、炎症、肾小管损伤和氧化应激。 qPCR 分析显示，与注射 pCAG-EGFP 的 UUO 肾脏相比，注射 pCAG-APE1 的动物中 Casp3 和炎症相关基因的表达显着降低。 RNA-Seq分析表明，注射pCAG-APE1的UUO肾脏中的主要转录变化与免疫系统过程、代谢过程、催化活性和细胞凋亡相关，从而导致正常的肾脏修复。因此，APE1 不仅通过抗氧化和 DNA 修复功能来抑制肾纤维化，还部分通过包括 IL6、Tnf 和趋化因子家族在内的多种途径调节免疫系统。因此，治疗性 APE1 调节可能有益于肾脏疾病的治疗。
Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that controls the cellular response to oxidative stress and possesses DNA-repair functions. It has important roles in the progression and outcomes of various diseases; however, its function and therapeutic prospects with respect to kidney injury are unknown. To study this, we activated APE1 during kidney injury by constructing an expression vector (pCAG-APE1), using an EGFP expression plasmid (pCAG-EGFP) as a control. We performed unilateral ureteral obstruction (UUO) as a model of tubulointerstitial fibrosis on ICR mice before each vector was administrated via retrograde renal vein injection. In this model, pCAG-APE1 injection did not produce any adverse effects and significantly reduced histological end points including fibrosis, inflammation, tubular injury, and oxidative stress, as compared to those parameters after pCAG-EGFP injection. qPCR analysis showed significantly lower expression ofCasp3and inflammation-related genes in pCAG-APE1-injected animals compared to those in pCAG-EGFP-injected UUO kidneys. RNA-Seq analyses showed that the major transcriptional changes in pCAG-APE1-injected UUO kidneys were related to immune system processes, metabolic processes, catalytic activity, and apoptosis, leading to normal kidney repair. Therefore, APE1 suppressed renal fibrosis, not only via antioxidant and DNA-repair functions, but also partly by modulating the immune system through multiple pathways includingIl6,Tnf, and chemokine families. Thus, therapeutic APE1 modulation might be beneficial for the treatment of renal diseases.