Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease
Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease
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DOI：
10.1681/asn.2011010046
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发表时间：
2012-01-01
影响因子：
13.6
通讯作者：
Noronha, Irene L.
中科院分区：
文献类型：
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作者：
Delle, Humberto;Rocha, Jose Roberto C.;Noronha, Irene L.
他莫昔芬是一种选择性雌激素受体调节剂，具有抗纤维化的特性;然而，它是否能减轻肾纤维化尚不清楚。在这项研究中，我们测试了他莫昔芬在高血压肾硬化模型中的作用（用L-NAME慢性抑制一氧化氮合成）。30天后，与未治疗的对照组相比，治疗组大鼠的白蛋白尿水平显著降低，肾小球硬化和间质纤维化的组织学评分也降低。三苯氧胺对L-NAME引起的持续性、重度高血压无明显作用，但具有肾脏保护作用。他莫昔芬通过降低I型胶原、III型胶原和纤连蛋白mRNA和蛋白的表达来防止细胞外基质的积累。这些肾保护作用与TGF-β 1和纤溶酶原激活物抑制剂-1的抑制有关，并与肾髓质中α-平滑肌肌动蛋白阳性细胞的显著减少有关。此外，他莫昔芬废除IL-1 β和血管紧张素II诱导的成纤维细胞从肾脏外植体和NRK-49 F细胞系的增殖。他莫昔芬也抑制细胞外基质成分的表达和TGF-β 1的产生和释放到这些细胞的上清液中。总之，他莫昔芬在高血压肾硬化的L-NAME模型中表现出抗纤维化作用，可能是通过抑制TGF-β 1，这表明它可能在CKD治疗中具有治疗用途。
Tamoxifen, a selective estrogen receptor modulator, has antifibrotic properties; however, whether it can attenuate renal fibrosis is unknown. In this study, we tested the effects of tamoxifen in a model of hypertensive nephrosclerosis (chronic inhibition of nitric oxide synthesis with L-NAME). After 30 days, treated rats had significantly lower levels of albuminuria as well as lower histologic scores for glomerulosclerosis and interstitial fibrosis than untreated controls. Tamoxifen was renoprotective despite having no effect on the sustained, severe hypertension induced by L-NAME. Tamoxifen prevented the accumulation of extracellular matrix by decreasing the expression of collagen I, collagen III, and fibronectin mRNA and protein. These renoprotective effects associated with inhibition of TGF-beta 1 and plasminogen activator inhibitor-1, and with a significant reduction in a-smooth muscle actin-positive cells in the renal interstitium. Furthermore, tamoxifen abrogated IL-1 beta- and angiotensin-II-induced proliferation of fibroblasts from both kidney explants and from the NRK-49F cell line. Tamoxifen also inhibited the expression of extracellular matrix components and the production and release of TGF-beta 1 into the supernatant of these cells. In summary, tamoxifen exhibits antifibrotic effects in the L-NAME model of hypertensive nephrosclerosis, likely through the inhibition of TGF-beta 1, suggesting that it may have therapeutic use in CKD treatment.