First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Surgery. 2011 Jul;150(1):39-47. doi: 10.1016/j.surg.2011.02.019. Epub 2011 May 18.
Renal ischemia reperfusion injury induces gender-dependent heat-shock protein 72 expression, which maintains membrane localization of renal Na(+)/K(+)ATPase-α1. The erythropoietin has a protecting effect against ischemia reperfusion injury in various organs. In this study, we investigated whether erythropoietin exerts a beneficial effect against post-ischemic renal injury. Furthermore, we studied the erythropoietin signaling on heat-shock protein 72 and Na(+)/K(+)ATPase-α1 expression and localization.
In male and female Wistar rats, rHuEPO (1000 IU/bwkg intraperitoneal) or vehicle was administered 24 hours prior to unilateral left renal ischemia reperfusion (50 minutes). Kidneys were subsequently removed at hours 2 or 24 of the reperfusion; sham-operated rats served as controls (C) (n = 8/group). We measured serum erythropoietin, renal function, evaluated histological injury, and observed heat-shock protein 72 as well as Na(+)/K(+)ATPase-α1 protein level and localization. Additional groups were followed for 7-day survival.
Erythropoietin treatment was associated with better post-ischemic survival and less impaired renal function in males while diminishing the renal structural damage in both sexes. Endogenous erythropoietin was higher in males and increased in both genders after erythropoietin treatment. The erythropoietin treatment elevated protein levels of heat-shock protein 72 and Na(+)/K(+)ATPase-α1 in 24 hours in males, whereas in females, the already higher expression of heat-shock protein 72 and Na(+)/K(+)ATPase-α1 was not increased. Moreover, erythropoietin prevented ischemia reperfusion induced Na(+)/K(+)ATPase-α1 translocation from the basolaterale membrane in males.
Erythropoietin diminishes gender difference in the susceptibility to renal post-ischemic injury and reduces post-ischemic structural damage while preserving kidney function, particularly in males. This additional protection may be associated with a heat-shock protein 72-mediated effect on Na(+)/K(+)ATPase-α1 expression and translocation.
肾缺血再灌注损伤诱导性别依赖性热休克蛋白 72 表达，维持肾钠钾 ATP 酶-α1 的膜定位。促红细胞生成素对各种器官的缺血再灌注损伤具有保护作用。在这项研究中，我们研究了促红细胞生成素是否对缺血后肾损伤有有益作用。此外，我们研究了促红细胞生成素信号对热休克蛋白 72 和钠钾 ATP 酶-α1 表达和定位的影响。
在雄性和雌性 Wistar 大鼠中，在单侧左肾缺血再灌注（50 分钟）前 24 小时给予 rHuEPO（1000 IU/bwkg 腹腔内）或载体。再灌注后 2 或 24 小时取出肾脏；假手术大鼠作为对照（C）（n=8/组）。我们测量血清促红细胞生成素、肾功能，评估组织学损伤，并观察热休克蛋白 72 以及钠钾 ATP 酶-α1 蛋白水平和定位。另外的组进行了 7 天的生存随访。
促红细胞生成素治疗与雄性动物更好的缺血后生存和更少的肾功能损害相关，同时减少两性的肾结构损伤。内源性促红细胞生成素在雄性中较高，在两性中促红细胞生成素治疗后增加。促红细胞生成素治疗在 24 小时内提高了雄性的热休克蛋白 72 和钠钾 ATP 酶-α1 的蛋白水平，而在雌性中，热休克蛋白 72 和钠钾 ATP 酶-α1 的表达已经较高，没有增加。此外，促红细胞生成素防止了缺血再灌注诱导的钠钾 ATP 酶-α1 在雄性中的基底外侧膜易位。
促红细胞生成素降低了肾缺血后损伤易感性的性别差异，减少了缺血后结构损伤，同时保护了肾功能，特别是在雄性中。这种额外的保护可能与热休克蛋白 72 对钠钾 ATP 酶-α1 表达和易位的介导作用有关。
