Acquired resistance to rechallenge injury in rats that recovered from mild renal damage induced by uranyl acetate : accelerated proliferation and hepatocyte growth factor/c-Met axis.
Acquired resistance to rechallenge injury in rats that recovered from mild renal damage induced by uranyl acetate : accelerated proliferation and hepatocyte growth factor/c-Met axis.
复制标题
从醋酸双氧铀引起的轻度肾损伤中恢复的大鼠获得了对再攻击损伤的抵抗力：加速增殖和肝细胞生长因子/c-Met轴。
DOI：
10.1007/s10157-011-0453-x
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发表时间：
2011
期刊：
影响因子：
2.3
通讯作者：
Hishida A
中科院分区：
文献类型：
--
作者：
Sun Y;Fujigaki Y;Sakakima M;Fujikura T;Togawa A;Huang Y;Hishida A
研究背景近端小管(PT)轻度损伤后恢复的大鼠，在亚毒性损伤后无肾功能障碍，对随后的肾毒性损伤产生部分抵抗。与首次使用赋形剂治疗相比，这种部分抵抗与减少肾功能障碍和加速PT细胞增殖有关。在此，我们探讨了PT增殖加速在获得性耐药模型中的作用及其可能的机制。方法用0.2 mg/kg醋酸铀酰(UA)(亚毒性剂量)诱导的轻度肾损伤恢复14天后，用4 mg/kg UA(肾毒性剂量)再次激发大鼠建立获得性耐药模型。通过体内溴脱氧尿嘧啶核苷(BrdU)标记，观察秋水仙碱抑制PT细胞增殖对获得性肾毒性抵抗的作用。结果轻度肾损伤后恢复的大鼠对肾毒性再激发损伤的获得性抵抗与BrdU阳性的PT细胞较早增加、HGF mRNA、c-Met mRNA/蛋白、细胞周期蛋白D1和磷酸化Rb的上调以及PT细胞表型的早期改变有关。秋水仙碱抑制PT细胞增殖，减少肾脏细胞周期蛋白D1和磷酸化Rb的表达，完全消除获得性抵抗。结论HGF/c-Met轴上调的细胞周期进程可能有助于急性肾功能衰竭大鼠早期轻度肾损伤恢复，继而出现肾毒性损害，导致部分获得性抵抗。
BackgroundRats that recovered from mild proximal tubule (PT) injury without renal dysfunction by subtoxic insult, developed partial resistance to subsequent nephrotoxic insult. This partial resistance was associated with reduced renal dysfunction and accelerated PT cell proliferation compared with vehicle treatment as the first insult. Here we assessed the role and potential mechanisms of accelerated PT proliferation in this acquired resistance model.MethodsRats at 14 days after recovering from prior mild renal damage induced by 0.2 mg/kg uranyl acetate (UA) (subtoxic dose) were rechallenged with 4 mg/kg UA (nephrotoxic dose) to establish the acquired resistance model. Cell cycle was inhibited by colchicine to examine the contribution of accelerated PT cell proliferation evaluated by in vivo bromodeoxyuridine (BrdU) labeling on acquired resistance to subsequent nephrotoxic insult. Hepatocyte growth factor (HGF)/c-Met axis and other related factors of cell cycle were analyzed.ResultsThe acquired resistance to rechallenge injury with nephrotoxic dose of UA in rats recovered from mild renal injury was associated with an earlier increase in BrdU-positive PT cells, accelerated upregulation of HGF mRNA, c-Met mRNA/protein, cyclin D1, phospho-Rb and an earlier phenotypic change of PT cells. Colchicine inhibited PT cell proliferation, reduced the upregulated cyclin D1 and phospho-Rb in the kidney, completely abolishing acquired resistance.ConclusionsCell cycle progression with upregulated renal HGF/c-Met axis may contribute to the accelerated recovery from acute renal failure in rats that recovered from prior mild renal damage, followed by nephrotoxic insult, resulting in partial acquired resistance.