骨髓
纤维化
STAT6
肾
成纤维细胞
癌症研究
细胞外基质
肌成纤维细胞
肺纤维化
医学
病理
化学
内分泌学
内科学
生物
细胞生物学
白细胞介素4
细胞因子
体外
生物化学
作者
Jingyin Yan,Zhengmao Zhang,Jun Yang,William E. Mitch,Yanlin Wang
出处
期刊:Journal of The American Society of Nephrology
日期:2015-12-01
卷期号:26 (12): 3060-3071
被引量:91
标识
DOI:10.1681/asn.2014070717
摘要
Renal fibrosis is a final common manifestation of CKD resulting in progressive loss of kidney function. Bone marrow–derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow–derived fibroblast precursors in the kidney are not fully understood. In this study, we investigated the role of the Janus kinase 3 (JAK3)/signal transducer and activator of transcription (STAT6) signaling pathway in the activation of bone marrow–derived fibroblasts. In cultured mouse monocytes, IL-4 or IL-13 activated STAT6 and induced expression of α-smooth muscle actin and extracellular matrix proteins (fibronectin and collagen I), which was abolished by a JAK3 inhibitor (CP690,550) in a dose-dependent manner or blocked in the absence of STAT6. In vivo, STAT6 was activated in interstitial cells of the obstructed kidney, an effect that was abolished by CP690,550. Mice treated with CP690,550 accumulated fewer bone marrow–derived fibroblasts in the obstructed kidneys compared with vehicle-treated mice. Treatment with CP690,550 also significantly reduced myofibroblast transformation, matrix protein expression, fibrosis development, and apoptosis in obstructed kidneys. Furthermore, STAT6-deficient mice accumulated fewer bone marrow–derived fibroblasts in the obstructed kidneys, produced less extracellular matrix protein, and developed much less fibrosis. Finally, wild-type mice engrafted with STAT6−/− bone marrow cells displayed fewer bone marrow–derived fibroblasts in the obstructed kidneys and showed less severe renal fibrosis compared with wild-type mice engrafted with STAT6+/+ bone marrow cells. Our results demonstrate that JAK3/STAT6 has an important role in bone marrow–derived fibroblast activation, extracellular matrix production, and interstitial fibrosis development.
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