The renin-angiotensin system contributes to renal fibrosis through regulation of fibrocytes
The renin-angiotensin system contributes to renal fibrosis through regulation of fibrocytes
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DOI：
10.1097/hjh.0b013e3282f3e9e6
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发表时间：
2008-04-01
影响因子：
4.9
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
--
作者：
Sakai, Norihiko;Wada, Takashi;Kaneko, Shuichi
肾素-血管紧张素系统是心血管和肾脏疾病发病的重要途径。骨髓源性纤维细胞CD45和I型胶原双阳性，目前被认为与多种纤维化疾病的发病机制有关。我们假设纤维细胞可能通过血管紧张素II依赖性途径导致肾纤维化。结果在小鼠肾纤维化模型中，与野生型小鼠相比，血管紧张素II 2型受体（AT2R）缺陷小鼠的肾纤维化和纤维细胞浸润增加，同时I型前胶原(a) （COL1A1）的肾转录物上调。at2r缺陷小鼠骨髓纤维细胞数量也增加。相比之下，缬沙坦对血管紧张素II型1受体（AT1R）的药理抑制降低了肾纤维化程度和肾脏和骨髓中纤维细胞的数量。在分离的人纤维细胞中，抑制AT2R信号会增加血管紧张素ii刺激的I型胶原的表达，而抑制AT1R则会减少胶原合成。这些结果表明，AT1R/AT2R信号可能通过至少两种机制参与肾纤维化的发病机制：通过调节骨髓中纤维细胞的数量，以及通过激活纤维细胞。
Background The renin-angiotensin system is a major pathway in the pathogenesis of cardiovascular and renal diseases. Bone marrow-derived fibrocytes, which are dual positive for CD45 and type I collagen, are now considered to contribute to the pathogenesis of various fibrotic diseases. We hypothesized that fibrocytes might contribute to renal fibrosis by an angiotensin II dependent pathway.Results In murine models of renal fibrosis, angiotensin II type 2 receptor (AT2R)-deficient mice, when compared with wild-type mice, showed increased renal fibrosis and fibrocyte infiltration with a concomitant upregulation of renal transcripts of procollagen type I ( a) (COL1A1). Fibrocyte numbers in the bone marrow also were increased in AT2R-deficient mice. By contrast, pharmacological inhibition of angiotensin II type 1 receptor (AT1R) with valsartan reduced the degree of renal fibrosis and the number of fibrocytes in both the kidney and the bone marrow. In isolated human fibrocytes, inhibition of AT2R signaling increased the angiotensin II-stimulated expression of type I collagen, whereas inhibition of AT1R decreased collagen synthesis. These results suggest that AT1R/AT2R signaling may contribute to the pathogenesis of renal fibrosis by at least two mechanisms: by regulating the number of fibrocytes in the bone marrow, and by activation of fibrocytes.