The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice
The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice
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DOI：
10.1038/ki.2010.535
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发表时间：
2011-05-01
影响因子：
19.6
通讯作者：
Hughes, Jeremy
中科院分区：
文献类型：
--
作者：
Ferenbach, David A.;Nkejabega, Noemie C. J.;Hughes, Jeremy
增龄被认为与肾脏缺血再灌注损伤(IRI)的易感性增加有关。为了研究血红素加氧酶-1(HO-1，一种保护和抗炎的酶)的诱导缺陷是否与此有关，我们发现，尽管12个月龄的小鼠具有相似的基础肾功能和HO-1的表达，但通常在缺血-再灌注时出现的HO-1的诱导减少。与年轻小鼠相比，这也与老年小鼠肾功能恶化和急性肾小管坏死有关。在老年小鼠中，血红素精氨酸(HA)诱导皮质和髓质中的HO-1，显著改善肾功能，减少组织损伤。细胞HO-1对损伤或HA处理的反应被发现是间质的而不是上皮性的，其与巨噬细胞标志的共存证明了这一点。在体外，HA处理原代巨噬细胞可显著诱导HO-1，而不损害经典的激活途径。12月龄CD11b-DTR转基因动物白喉毒素处理引起巨噬细胞耗竭，导致间质HO-1阳性细胞丢失，HA处理的保护性表型逆转。因此，肾脏IRI后HO-1的诱导失败会加重老年小鼠的结构和功能损伤，并代表着老年人的治疗靶点。因此，HO-1阳性的肾巨噬细胞介导了HA对IRI的保护作用。国际肾脏杂志(2011年)79966-976；doi：10.1038/ki.2010.535；2011年1月19日在线发布
Aging is thought to be associated with a higher susceptibility to renal ischemia-reperfusion injury (IRI). To study whether defective induction of hemeoxygenase-1 (HO-1, a protective and anti-inflammatory enzyme) might contribute to this, we found that while 12-month-old mice had similar baseline renal function and HO-1 expression, the induction of HO-1 usually seen in ischemia-reperfusion was reduced. This was also associated with worsened renal function and acute tubular necrosis in the aged compared with young mice. In the older mice, heme arginate (HA) induced HO-1 in the cortex and medulla, significantly improved renal function, and reduced tissue injury. Cellular HO-1 induction in the medulla in response to injury or HA treatment was found to be interstitial rather than epithelial, as evidenced by its colocalization with macrophage markers. In vitro, HA treatment of primary macrophages resulted in marked HO-1 induction without impairment of classical activation pathways. Macrophage depletion, caused by diphtheria toxin treatment of 12-month-old CD11b-DTR transgenic animals, resulted in the loss of interstitial HO-1-positive cells and reversal of the protective phenotype of HA treatment. Thus, failure of HO-1 induction following renal IRI worsens structural and functional injury in older mice and represents a therapeutic target in the elderly. Hence, HO-1-positive renal macrophages mediate HA-induced protection in IRI. Kidney International (2011) 79, 966-976; doi:10.1038/ki.2010.535; published online 19 January 2011