Critical role of CXCL16 in hypertensive kidney injury and fibrosis.
Critical role of CXCL16 in hypertensive kidney injury and fibrosis.
复制标题
DOI：
10.1161/hypertensionaha.113.01837
复制
发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Xia Y;Entman ML;Wang Y
最近的证据表明，炎症在高血压肾病的发生和发展中起着至关重要的作用。然而，诱导炎症的信号传导机制知之甚少。我们发现CXCL 16在肾小管上皮细胞中以NF-κ B依赖的方式响应于血管紧张素II而被诱导。为了确定CXCL 16是否在血管紧张素II诱导的肾脏炎症和纤维化中起作用，将野生型和CXCL 16敲除小鼠以1500 ng/kg/min的血管紧张素II输注长达4周。野生型和CXCL 16敲除小鼠在基线时具有相当的血压。血管紧张素II治疗导致血压升高，这在WT和CXCL 16敲除小鼠之间是相似的。CXCL 16基因敲除小鼠可避免血管紧张素II诱导的肾功能障碍、蛋白尿和纤维化。CXCL 16缺乏抑制骨髓来源的成纤维细胞的积累和肌成纤维细胞的形成，在肾脏血管紧张素II治疗的小鼠，这是与细胞外基质蛋白的表达减少。此外，与野生型小鼠相比，CXCL 16缺乏抑制血管紧张素II治疗小鼠肾脏中F4/80+巨噬细胞和CD 3 + T细胞的浸润。最后，CXCL 16缺乏减少了肾脏中血管紧张素II诱导的促炎细胞因子表达。总之，我们的研究结果表明，CXCL 16通过调节巨噬细胞和T细胞浸润以及骨髓源性成纤维细胞积累在血管紧张素II诱导的肾损伤和纤维化的发病机制中起着关键作用。
Recent evidence indicates that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that CXCL16 was induced in renal tubular epithelial cells in response to angiotensin II in a NF-κB-dependent manner. To determine if CXCL16 plays a role in angiotensin II-induced renal inflammation and fibrosis, wild-type and CXCL16 knockout mice were infused with angiotensin II at 1500 ng/kg/min for up to 4 weeks. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Angiotensin II treatment led to an increase in blood pressure that was similar between WT and CXCL16 knockout mice. CXCL16 knockout mice were protected from angiotensin II-induced renal dysfunction, proteinuria, and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidneys of angiotensin II-treated mice, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80+ macrophages and CD3+ T cells in the kidneys of angiotensin II-treated mice compared with wild-type mice. Finally, CXCL16 deficiency reduced angiotensin II-induced proinflammatory cytokine expressions in the kidneys. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of angiotensin II-induced renal injury and fibrosis through regulation of macrophage and T cell infiltration and bone marrow-derived fibroblast accumulation.