Institut für Physiologie, Universität Regensburg, Universitätsstr. 31, D-93040 Regensburg, Germany.
Am J Physiol Renal Physiol. 2010 Jan;298(1):F196-204. doi: 10.1152/ajprenal.90607.2008. Epub 2009 Oct 14.
Acute renal failure (ARF) is frequently associated with polyuria and urine concentration defects and it is a severe complication of sepsis because it increases the mortality rate. Inhibition of NF-kappaB activation has been suggested to provide a useful strategy for the treatment of septic shock. However, the impact on sepsis-induced ARF is still unclear. Therefore, we examined the effect of pyrrolidine dithiocarbamate (PDTC) and of small interfering RNA (siRNA) silencing NF-kappaB p50/p105 on sepsis-induced downregulation of vasopressin V(2) receptors and aquaporin (AQP)-2 channels using a cecal ligation and puncture (CLP) mouse model. CLP caused a time-dependent downregulation of renal vasopressin V(2) receptor and of AQP2 expression without alterations in plasma vasopressin levels. Renal activation of NF-kappaB in response to CLP was attenuated by PDTC pretreatment, which also attenuated the downregulation of V(2) receptor and AQP2 expression. Furthermore, a strong nuclear staining for the NF-kappaB p50 subunit throughout the whole kidney in response to CLP was observed. siRNA against NF-kappaB p50 attenuated the CLP-induced nuclear translocation of the p50 subunit and the CLP-induced downregulation of V(2) receptor and AQP2 expression. Additionally, PDTC and siRNA pretreatment inhibited the CLP-induced increase in renal TNF-alpha and IL-1beta concentration and NOS-2 mRNA abundance. Moreover, PDTC and siRNA pretreatment ameliorated CLP-induced hypotension and ARF. Our findings suggest that NF-kappaB activation is of importance for the downregulation of AQP2 channel and vasopressin V(2) receptor expression during sepsis. In addition, our data indicate that NF-kappaB inhibition ameliorates sepsis-induced ARF.
急性肾衰竭（ARF）常伴有多尿和尿液浓缩缺陷，是脓毒症的严重并发症，因为它会增加死亡率。抑制 NF-κB 激活被认为是治疗感染性休克的一种有效策略。然而，其对脓毒症引起的 ARF 的影响尚不清楚。因此，我们使用盲肠结扎穿孔（CLP）小鼠模型，研究吡咯烷二硫代氨基甲酸盐（PDTC）和小干扰 RNA（siRNA）沉默 NF-κB p50/p105 对脓毒症诱导的血管加压素 V2 受体和水通道蛋白（AQP）-2 通道下调的影响。CLP 导致肾血管加压素 V2 受体和 AQP2 表达随时间呈下调趋势，而血浆血管加压素水平没有变化。CLP 引起的 NF-κB 肾激活通过 PDTC 预处理减弱，这也减弱了 V2 受体和 AQP2 表达的下调。此外，还观察到整个肾脏 NF-κB p50 亚基对 CLP 的强烈核染色。针对 NF-κB p50 的 siRNA 减弱了 CLP 诱导的 p50 亚基核易位以及 CLP 诱导的 V2 受体和 AQP2 表达下调。此外，PDTC 和 siRNA 预处理抑制了 CLP 诱导的肾 TNF-α和 IL-1β浓度和 NOS-2 mRNA 丰度增加。此外，PDTC 和 siRNA 预处理改善了 CLP 诱导的低血压和 ARF。我们的研究结果表明，NF-κB 激活对于脓毒症期间 AQP2 通道和血管加压素 V2 受体表达的下调很重要。此外，我们的数据表明 NF-κB 抑制可改善脓毒症引起的 ARF。
