音猬因子
环胺
胶质1
平滑
肾
成纤维细胞
细胞生物学
纤维化
肌成纤维细胞
内分泌学
内科学
刺猬信号通路
生物
癌症研究
病理
成纤维细胞生长因子
医学
信号转导
受体
生物化学
体外
作者
Dong Zhou,Yingjian Li,Lili Zhou,Roderick J. Tan,Xiao Jun Lin,Min Liang,Fan Fan Hou,Youhua Liu
出处
期刊:Journal of The American Society of Nephrology
日期:2014-10-01
卷期号:25 (10): 2187-2200
被引量:115
标识
DOI:10.1681/asn.2013080893
摘要
Tubular epithelium constitutes the majority of the renal parenchyma and is the primary target of various kidney injuries. However, how the injured tubules drive interstitial fibroblast activation and proliferation remains poorly understood. Here, we investigated the role of sonic hedgehog (Shh), a secreted extracellular signaling protein, in fibroblast proliferation. Shh was induced in renal tubular epithelia in animal models of CKD induced by ischemia/reperfusion injury (IRI), adriamycin, or renal mass ablation, and in renal tubules of kidney biopsy specimens from CKD patients with different etiologies. Using Gli1-CreER(T2) reporter mice, we identified interstitial fibroblasts as the principal targets of renal Shh signaling in vivo. In vitro, incubation with Shh promoted normal rat kidney fibroblast proliferation, which was assessed by cell counting, MTT assay, and BrdU incorporation assay, and stimulated the induction of numerous proliferation-related genes. However, Shh had no effect on the proliferation of renal tubular epithelial cells. In vivo, overexpression of Shh promoted fibroblast expansion and aggravated kidney fibrotic lesions after IRI. Correspondingly, blockade of Shh signaling by cyclopamine, a small molecule inhibitor of Smoothened, inhibited fibroblast proliferation, reduced myofibroblast accumulation, and attenuated renal fibrosis. These studies identify Shh as a novel, specific, and potent tubule-derived growth factor that promotes interstitial fibroblast proliferation and activation. Our data also suggest that blockade of Shh signaling is a plausible strategy for therapeutic intervention of renal fibrosis.
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