Liu M, Agreda P, Crow M, Racusen L, Rabb H
Department of Medicine, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Transplant Proc. 2009 Dec;41(10):4065-71. doi: 10.1016/j.transproceed.2009.08.083.
Ischemia reperfusion injury (IRI) has long-term sequelae on kidney allograft function. Early initiation of rapamycin can retard surgical wound healing and recovery from IRI. In contrast, rapamycin may paradoxically retard long-term fibrotic effects of kidney IRI. We, therefore, hypothesized that delayed initiation of rapamycin after kidney ischemia, started after the initial week of wound healing, would decrease the long-term inflammation and fibrosis caused by IRI. C57BL/6 male mice were subjected to either 45 or 60 minutes of unilateral kidney ischemia or a sham operation. Mice were given rapamycin (subcutaneous, 1.5 mg/kg/d) or vehicle starting at 1 week after IRI surgery for 3 weeks. Urine albumin excretion, kidney histology, and kidney cytokine proteins were examined at 4 weeks after surgery. The 3-week treatment course of rapamycin significantly reduced body weight gain in all 3 groups and reduced postischemic kidney weight in both the 45- and 60-minute ischemia groups, but unexpectedly increased urine albumin excretion in all rapamycin-treated sham or IRI mice compared with vehicle-treated mice. Rapamycin treatment showed minimal effects on postischemic kidney fibrosis with variable effects on various cytokine/chemokine protein expressions, namely, decreasing interleukin (IL)-1alpha, IL-6, tumor necrosis factor (TNF)-alpha, and regulated on activation normal T cell expressed and secreted (RANTES) while increasing IL-4, keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP-1alpha), and IL-10 in the ischemic kidney. These data demonstrated that rapamycin reduced mouse body weight and ischemic kidney weight, while increasing urinary albumin excretion. Delayed initiation of rapamycin after IRI had a minimal effect on renal fibrosis and mixed effects on proinflammatory mediator production. These data do not support delayed initiation of rapamycin after IRI to attenuate IRI-induced progressive fibrosis and inflammation, and They raise further caution regarding rapamycin and albuminuria.
缺血再灌注损伤（IRI）对肾移植功能有长期后遗症。雷帕霉素的早期使用会延缓手术伤口愈合以及从IRI中的恢复。相比之下，雷帕霉素可能反常地延缓肾IRI的长期纤维化效应。因此，我们假设在肾脏缺血后延迟开始使用雷帕霉素，即在伤口愈合的第一周后开始使用，会减少IRI引起的长期炎症和纤维化。将C57BL/6雄性小鼠进行45或60分钟的单侧肾脏缺血或假手术。在IRI手术后1周开始，给小鼠皮下注射雷帕霉素（1.5mg/kg/d）或赋形剂，持续3周。在手术后4周检查尿白蛋白排泄、肾脏组织学和肾脏细胞因子蛋白。雷帕霉素3周的治疗疗程显著降低了所有3组的体重增加，并降低了45分钟和60分钟缺血组缺血后肾脏的重量，但与赋形剂处理的小鼠相比，所有雷帕霉素处理的假手术或IRI小鼠的尿白蛋白排泄意外增加。雷帕霉素治疗对缺血后肾脏纤维化的影响最小，对各种细胞因子/趋化因子蛋白表达有不同影响，即降低白细胞介素（IL）-1α、IL-6、肿瘤坏死因子（TNF）-α和正常T细胞激活后表达和分泌的调节趋化因子（RANTES），同时增加缺血肾脏中的IL-4、角质形成细胞衍生趋化因子（KC）、巨噬细胞炎性蛋白（MIP-1α）和IL-10。这些数据表明雷帕霉素降低了小鼠体重和缺血肾脏重量，同时增加了尿白蛋白排泄。IRI后延迟开始使用雷帕霉素对肾纤维化的影响最小，对促炎介质产生有混合影响。这些数据不支持IRI后延迟开始使用雷帕霉素以减轻IRI诱导的进行性纤维化和炎症，并且它们进一步引发了对雷帕霉素和蛋白尿的关注。
