Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death
Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death
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DOI：
10.1074/jbc.m110927200
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发表时间：
2002-03-29
影响因子：
4.8
通讯作者：
Robey, RB
中科院分区：
文献类型：
--
作者：
Bryson, JM;Coy, PE;Robey, RB
葡萄糖（Glc）代谢可保护细胞免受氧化损伤。鉴于己糖激酶（HKs）在葡萄糖摄取和利用中都处于核心地位，它们非常适合对这些效应产生作用。与这一假设相符的是，内源性己糖激酶活性与单个肾细胞类型的损伤易感性呈负相关。我们最近报道，异位己糖激酶表达模拟了培养的成纤维细胞中生长因子的抗凋亡作用，但己糖激酶的抗凋亡作用尚未在其他细胞类型或细胞损伤模型中进行研究。因此，我们在一个已建立的上皮细胞培养损伤模型中评估了己糖激酶过表达减轻急性氧化剂诱导的细胞死亡的能力。同时，我们研究了有益的肝素结合表皮生长因子（EGF）样生长因子（HB - EGF）处理的以下能力：1）增加内源性己糖激酶活性；2）模拟异位己糖激酶表达的保护作用。己糖激酶过表达和HB - EGF都增加了葡萄糖磷酸化能力和代谢，并且这些变化与对急性氧化剂诱导的凋亡的敏感性显著降低有关。这些效应对葡萄糖的一致依赖性表明，葡萄糖代谢，特别是己糖激酶活性，在促进上皮细胞存活方面具有重要的适应性作用。这些发现也支持了己糖激酶对生长因子的保护作用有贡献这一论点。
Glucose (Glc) metabolism protects cells against oxidant injury. By virtue of their central position in both Glc uptake and utilization, hexokinases (HKs) are ideally suited to contribute to these effects. Compatible with this hypothesis, endogenous HK activity correlates inversely with injury susceptibility in individual renal cell types. We recently reported that ectopic HK expression mimics the anti-apoptotic effects of growth factors in cultured fibroblasts, but anti-apoptotic roles for HKs have not been examined in other cell types or in a cellular injury model. We therefore evaluated HK overexpression for the ability to mitigate acute oxidant-induced cell death in an established epithelial cell culture injury model. In parallel, we examined salutary heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) treatment for the ability to 1) increase endogenous HK activity and 2) mimic the protective effects of ectopic H-K expression. Both HK overexpression and HB-EGF increased Glc-phosphorylating capacity and metabolism, and these changes were associated with markedly reduced susceptibility to acute oxidant-induced apoptosis. The uniform Glc dependence of these effects suggests an important adaptive role for Glc metabolism, and for HK activity in particular, in the promotion of epithelial cell survival. These findings also support the contention that HKs contribute to the protective effects of growth factors.