Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury
Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury
复制标题
DOI：
10.1152/ajprenal.00271.2014
复制
发表时间：
2014-08-15
影响因子：
4.2
通讯作者：
Schnellmann, Rick G.
中科院分区：
文献类型：
--
作者：
Smith, Joshua A.;Stallons, L. Jay;Schnellmann, Rick G.
虽然能量产生的中断是肾损伤的一个重要因素，但脓毒症诱导的阿基的代谢改变仍未得到充分研究。我们评估了脓毒症诱导的阿基小鼠模型中肾皮质糖酵解代谢的变化。在LPS暴露后3 h观察到己糖激酶（HK）活性的特异性和快速增加（类似于2倍），并维持至18 h，与通过血尿素氮（BUN）测定的肾功能下降相关。LPS诱导的HK激活独立于HK亚型表达或线粒体定位发生。未观察到糖酵解酶的其他变化。LPS介导的HK激活不足以增加糖酵解通量，如肾皮质中丙酮酸和乳酸水平降低或不变所示。LPS诱导的HK激活与葡萄糖-6-磷酸脱氢酶活性增加有关，但与糖原产生无关。从机制上讲，LPS诱导的HK激活被EGF受体（EGFR）和Akt的药理学抑制剂减弱，表明EGFR/磷脂酰肌醇3-激酶/Akt信号传导是负责的。我们的研究结果显示LPS以EGFR和Akt依赖的方式迅速增加肾皮质HK活性，HK活化与戊糖磷酸途径活性增加有关。
While disruption of energy production is an important contributor to renal injury, metabolic alterations in sepsis-induced AKI remain understudied. We assessed changes in renal cortical glycolytic metabolism in a mouse model of sepsis-induced AKI. A specific and rapid increase in hexokinase (HK) activity (similar to 2-fold) was observed 3 h after LPS exposure and maintained up to 18 h, in association with a decline in renal function as measured by blood urea nitrogen (BUN). LPS-induced HK activation occurred independently of HK isoform expression or mitochondrial localization. No other changes in glycolytic enzymes were observed. LPS-mediated HK activation was not sufficient to increase glycolytic flux as indicated by reduced or unchanged pyruvate and lactate levels in the renal cortex. LPS-induced HK activation was associated with increased glucose-6-phosphate dehydrogenase activity but not glycogen production. Mechanistically, LPS-induced HK activation was attenuated by pharmacological inhibitors of the EGF receptor (EGFR) and Akt, indicating that EGFR/phosphatidylinositol 3-kinase/Akt signaling is responsible. Our findings reveal LPS rapidly increases renal cortical HK activity in an EGFR-and Akt-dependent manner and that HK activation is linked to increased pentose phosphate pathway activity.