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Senolytic therapy ameliorates renal fibrosis postacute kidney injury by alleviating renal senescence
The FASEB Journal ( IF 4.8 ) Pub Date : 2020-12-24 , DOI: 10.1096/fj.202001855rr
Caizhen Li 1 , Yanting Shen 1 , Liuwei Huang 1 , Chongbin Liu 1 , Jun Wang 1
Affiliation  

Acute kidney injury (AKI) is a common clinical problem, and patients who survive AKI have a high risk of chronic kidney disease (CKD). The mechanism of CKD post‐AKI, characterized by progressive renal fibrosis, is still unclear. Maladaptive tubular epithelial cells (TECs) after AKI are considered a leading cause of renal fibrosis post‐AKI. TECs under maladaptive repair manifest characteristics of senescence. Removing senescent TECs by genetic ablation has been proven effective in reducing renal fibrosis. Senolytics, which eliminate senescent cells by pharmacological intervention, have been studied in a series of degenerative diseases. To our knowledge, the effects of senolytics on renal fibrosis post‐AKI have not been verified before. Here, we confirmed renal senescence in the unilateral ischemia/reperfusion injury murine model. Senescent TECs could activate fibroblasts and senolytics specifically induced apoptosis of senescent TECs. Next, we demonstrated that senolytics could reduce renal senescence and ameliorate renal fibrosis in both unilateral renal ischemia/reperfusion injury and multiple‐cisplatin‐treatment murine models. Our results indicate senescent TECs as a vital factor in renal fibrosis progression, and senolytic therapy might be promising for treating CKD post‐AKI.

中文翻译:

Senolytic疗法通过减轻肾衰老来改善急性肾损伤后的肾纤维化

急性肾损伤 (AKI) 是一种常见的临床问题,AKI 存活的患者患慢性肾病 (CKD) 的风险很高。以进行性肾纤维化为特征的 CKD 后 AKI 的机制尚不清楚。AKI 后适应不良的肾小管上皮细胞 (TEC) 被认为是 AKI 后肾纤维化的主要原因。适应不良修复下的 TECs 表现出衰老特征。通过基因消融去除衰老的 TECs 已被证明可有效减少肾纤维化。通过药理干预消除衰老细胞的 Senolytics 已在一系列退行性疾病中得到研究。据我们所知,senolytics 对 AKI 后肾纤维化的影响以前尚未得到证实。在这里,我们在单侧缺血/再灌注损伤小鼠模型中证实了肾脏衰老。衰老的 TECs 可以激活成纤维细胞,senolytics 特异性地诱导衰老的 TECs 凋亡。接下来,我们证明了在单侧肾缺血/再灌注损伤和多种顺铂治疗小鼠模型中,senolytics 可以减少肾脏衰老和改善肾脏纤维化。我们的结果表明,衰老的 TECs 是肾纤维化进展的一个重要因素,而 senolytic 疗法可能有望用于治疗 AKI 后的 CKD。
更新日期:2020-12-24
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