A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis
A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis
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DOI：
10.1681/asn.2006060604
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发表时间：
2007-02-01
影响因子：
13.6
通讯作者：
Nikolic-Paterson, David J.
中科院分区：
文献类型：
--
作者：
Ma, Frank Y.;Flanc, Robert S.;Nikolic-Paterson, David J.
肾脏纤维化和肾小管细胞凋亡是肾脏疾病进展的常见机制。体外研究表明，c-Jun氨基末端激酶（JNK）通路参与了这些过程。两种主要的JNK亚型，JNK 1和JNK 2，都在肾脏中表达，但它们对JNK信号传导的相对贡献是未知的。本研究使用两种不同的方法研究了JNK信号传导在单侧输尿管梗阻模型中肾纤维化和肾小管凋亡中的作用：（1）JNK 1或JNK 2缺陷的小鼠和（2）所有JNK亚型的特异性抑制剂CC-401。蛋白质印迹和免疫染色确定了阻塞肾脏中JNK信号的显著增加，JNK 1和JNK 2亚型之间存在大量冗余。CC-401的给药阻断了大鼠梗阻性肾脏中的JNK信号传导，并在间质肌成纤维细胞积聚和胶原IV沉积方面显著抑制了肾纤维化。这种效应归因于抑制促纤维化分子TGF-β 1和结缔组织生长因子的基因转录。CC-401治疗还显著减少了阻塞肾脏中的肾小管细胞凋亡。在单侧输尿管梗阻模型中，JNK 1或JNK 2的基因缺失不能保护小鼠免受肾纤维化，但JNK 1缺失确实导致肾小管细胞凋亡的显著减少。总之，这是第一个研究表明，JNK信号在肾纤维化和肾小管细胞凋亡中起着致病作用。此外，JNK 1在肾小管细胞凋亡中起着非冗余的作用。这些研究将JNK通路确定为进行性肾病的潜在治疗靶点。
Renal fibrosis and tubular apoptosis are common mechanisms of progressive kidney disease. In vitro studies have implicated the c-Jun amino-terminal kinase (JNK) pathway in these processes. Both of the major JNK isoforms, JNK1 and JNK2, are expressed in the kidney, but their relative contribution to JNK signaling is unknown. This study investigated the role of JNK signaling in renal fibrosis and tubular apoptosis in the unilateral ureteral obstruction model using two different approaches: (1) Mice that were deficient in either JNK1 or JNK2 and (2) a specific inhibitor of all JNK isoforms, CC-401. Western blotting and immunostaining identified a marked increase in JNK signaling in the obstructed kidney, with substantial redundancy between JNK1 and JNK2 isoforms. Administration of CC-401 blocked JNK signaling in the rat obstructed kidney and significantly inhibited renal fibrosis in terms of interstitial myofibroblast accumulation and collagen IV deposition. This effect was attributed to suppression of gene transcription for the profibrotic molecules TGF-beta 1 and connective tissue growth factor. CC-401 treatment also significantly reduced tubular apoptosis in the obstructed kidney. Genetic deletion of JNK1 or JNK2 did not protect mice from renal fibrosis in the unilateral ureteral obstruction model, but JNK1 deletion did result in a significant reduction in tubular cell apoptosis. In conclusion, this is the first study to demonstrate that JNK signaling plays a pathogenic role in renal fibrosis and tubular apoptosis. Furthermore, JNK1 plays a nonredundant role in tubular cell apoptosis. These studies identify the JNK pathway as a potential therapeutic target in progressive kidney disease.