Inhibition of IκB Kinase at 24 Hours After Acute Kidney Injury Improves Recovery of Renal Function and Attenuates Fibrosis.
Inhibition of IκB Kinase at 24 Hours After Acute Kidney Injury Improves Recovery of Renal Function and Attenuates Fibrosis.
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DOI：
10.1161/jaha.116.005092
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发表时间：
2017-07-03
影响因子：
5.4
通讯作者：
Thiemermann C
中科院分区：
文献类型：
--
作者：
Johnson FL;Patel NSA;Purvis GSD;Chiazza F;Chen J;Sordi R;Hache G;Merezhko VV;Collino M;Yaqoob MM;Thiemermann C
急性肾损伤（阿基）是慢性肾脏疾病发展的主要危险因素。核因子-κB是缺血后激活的核转录因子，负责促炎蛋白的转录。核因子-κB在阿基后肾纤维化中的作用尚不清楚。我们使用单侧肾切除术加对侧缺血（30分钟）和再灌注损伤（长达28天）引起的大鼠阿基模型，以显示肾功能受损（峰值：24小时）、核因子-κB活化（峰值：48小时）和纤维化（28天）。在人类中，阿基通过血清肌酐升高来诊断。我们发现IκB激酶抑制剂IKK 16（即使在血清肌酐峰值时给予）仍能改善功能和结构恢复，并减少肌成纤维细胞形成、巨噬细胞浸润、转化生长因子β表达和Smad 2/3磷酸化。阿基在28天内导致纤维化（天狼星红染色，纤连蛋白的表达），其被IKK 16消除。为了证实IKK 16在更严重的纤维化模型中的功效，使动物经受14天的单侧输尿管梗阻，导致肾小管间质纤维化、肌成纤维细胞形成和巨噬细胞浸润，所有这些都被IKK 16减弱。在肌酐峰值时抑制IκB激酶可改善功能恢复，减少进一步损伤，并预防纤维化。
Acute kidney injury (AKI) is a major risk factor for the development of chronic kidney disease. Nuclear factor‐κB is a nuclear transcription factor activated post‐ischemia, responsible for the transcription of proinflammatory proteins. The role of nuclear factor‐κB in the renal fibrosis post‐AKI is unknown. We used a rat model of AKI caused by unilateral nephrectomy plus contralateral ischemia (30 minutes) and reperfusion injury (up to 28 days) to show impairment of renal function (peak: 24 hours), activation of nuclear factor‐κB (peak: 48 hours), and fibrosis (28 days). In humans, AKI is diagnosed by a rise in serum creatinine. We have discovered that the IκB kinase inhibitor IKK16 (even when given at peak serum creatinine) still improved functional and structural recovery and reduced myofibroblast formation, macrophage infiltration, transforming growth factor‐β expression, and Smad2/3 phosphorylation. AKI resulted in fibrosis within 28 days (Sirius red staining, expression of fibronectin), which was abolished by IKK16. To confirm the efficacy of IKK16 in a more severe model of fibrosis, animals were subject to 14 days of unilateral ureteral obstruction, resulting in tubulointerstitial fibrosis, myofibroblast formation, and macrophage infiltration, all of which were attenuated by IKK16. Inhibition of IκB kinase at peak creatinine improves functional recovery, reduces further injury, and prevents fibrosis.