Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.
Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.
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DOI：
10.1371/journal.pone.0089355
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Tamaki T
中科院分区：
文献类型：
--
作者：
Ikeda Y;Ozono I;Tajima S;Imao M;Horinouchi Y;Izawa-Ishizawa Y;Kihira Y;Miyamoto L;Ishizawa K;Tsuchiya K;Tamaki T
肾纤维化在慢性肾脏疾病（CKD）的发生和发展中起着重要作用。虽然已经确定了肾纤维化的几种机制和治疗肾纤维化的候选药物，但铁螯合剂对肾纤维化的作用仍不清楚。在本研究中，我们研究了铁螯合剂去铁胺（DFO）对手术诱导的单侧输尿管梗阻（UUO）小鼠肾纤维化的影响。将小鼠分为4组：UUO加药组、UUO加DFO组、假药加药组、假药加DFO组。术后1周，UUO小鼠肾小管间质纤维化增强，ⅰ、ⅲ、ⅳ型胶原表达增加；DFO处理抑制了这些变化。同样，UUO小鼠经DFO处理后，UUO诱导的肾间质小管巨噬细胞浸润减少。DFO处理可消除uuo诱导的炎症因子和细胞外基质蛋白的表达。DFO抑制UUO小鼠转化生长因子-β1 (TGF-β1)-Smad3通路的激活。DFO降低了uuo诱导的NADPH氧化酶活性和p22phox的表达。UUO小鼠肾脏中二价金属转运蛋白1、铁转运蛋白和铁蛋白表达高于假手术小鼠，转铁蛋白受体表达低于假手术小鼠。UUO小鼠肾铁含量升高，DFO处理降低。这些结果表明，DFO减少铁通过调节TGF-β-Smad信号、氧化应激和炎症反应来预防肾小管间质纤维化。
Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22phox expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses.
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影响因子：
3
作者：
Grgic, Ivica;Duffield, Jeremy S.;Humphreys, Benjamin D.
通讯作者：
Humphreys, Benjamin D.
影响因子：
3.7
作者：
Ikeda Y;Tajima S;Izawa-Ishizawa Y;Kihira Y;Ishizawa K;Tomita S;Tsuchiya K;Tamaki T
通讯作者：
Tamaki T
DOI：
10.1152/ajprenal.2001.280.5.f803
发表时间：
2001-05-01
影响因子：
4.2
作者：
Ferguson, CJ;Wareing, M;Riccardi, D
通讯作者：
Riccardi, D
影响因子：
19.6
作者：
Ferguson, CJ;Wareing, M;Riccardi, D
通讯作者：
Riccardi, D
DOI：
10.2215/cjn.05980809
发表时间：
2009-12-01
影响因子：
9.8
作者：
Collins, Allan J.;Foley, Robert N.;Chen, Shu-Chen
通讯作者：
Chen, Shu-Chen