高糖可反式激活表皮生长因子受体，并上调近端小管中的血清糖皮质激素激酶。
High glucose transactivates the EGF receptor and up-regulates serum glucocorticoid kinase in the proximal tubule.
作者信息
Saad Sonia, Stevens Veronica A, Wassef Lesley, Poronnik Philip, Kelly Darren J, Gilbert Richard E, Pollock Carol A
机构信息
Kolling Institute Royal North Shore Hospital, University of Sydney, Sydney, Australia.
出版信息
Kidney Int. 2005 Sep;68(3):985-97. doi: 10.1111/j.1523-1755.2005.00492.x.
BACKGROUND
Serum glucocorticoid regulated kinase (SGK-1) is induced in the kidney in diabetes mellitus. However, its role in the proximal tubule is unclear. This study determined the expression and functional role of SGK-1 in PTCs in high glucose conditions. As the epidermal growth factor (EGF) receptor is activated by both EGF and other factors implicated in diabetic nephropathy, the relationship of SGK-1 with EGFR activity was assessed.
METHODS
mRNA and protein expression of SGK-1 and mRNA expression of the sodium hydrogen exchanger NHE3 were measured in human PTCs exposed to 5 mmol/L (control) and 25 mmol/L (high) glucose. The effects of SGK-1 on cell growth, apoptosis, and progression through the cell cycle and NHE3 mRNA were examined following overexpression of SGK-1 in PTCs. The role of EGFR activation in observed changes was assessed by phospho-EGFR expression, and response to the EGFR blocker PKI166. SGK-1 expression was then assessed in vivo in a model of streptozotocin-induced diabetes mellitus type 2.
RESULTS
A total of 25 mmol/L glucose and EGF (10 ng/mL) increased SGK-1 mRNA (P < 0.005 and P < 0.002, respectively) and protein (both P < 0.02) expression. High glucose and overexpression of SGK-1 increased NHE3 mRNA (P < 0.05) and EGFR phosphorylation (P < 0.01), which were reversed by PKI166. SGK-1 overexpression increased PTC growth (P < 0.0001), progression through the cell cycle (P < 0.001), and increased NHE3 mRNA (P < 0.01), which were all reversed with PKI166. Overexpression of SGK-1 also protected against apoptosis induced in the PTCs (P < 0.0001). Up-regulation of tubular SGK-1 mRNA in diabetes mellitus was confirmed in vivo. Oral treatment with PKI166 attenuated this increase by 51%. No EGF protein was detectable in PTCs, suggestive of phosphorylation of the EGFR by high glucose and downstream induction of SGK-1.
CONCLUSION
The effects of high glucose on PTC proliferation, reduced apoptosis and increased NHE3 mRNA levels are mediated by EGFR-dependent up-regulation of SGK-1.
背景
血清糖皮质激素调节激酶（SGK-1）在糖尿病患者的肾脏中被诱导产生。然而，其在近端小管中的作用尚不清楚。本研究确定了高糖条件下SGK-1在近端小管细胞（PTCs）中的表达及功能作用。由于表皮生长因子（EGF）受体可被EGF以及其他与糖尿病肾病相关的因子激活，因此评估了SGK-1与EGFR活性之间的关系。
方法
在暴露于5 mmol/L（对照）和25 mmol/L（高糖）葡萄糖的人PTCs中，测量SGK-1的mRNA和蛋白表达以及钠氢交换体NHE3的mRNA表达。在PTCs中过表达SGK-1后，检测SGK-1对细胞生长、凋亡、细胞周期进程以及NHE3 mRNA的影响。通过磷酸化EGFR表达以及对EGFR阻滞剂PKI166的反应，评估EGFR激活在观察到的变化中的作用。然后在链脲佐菌素诱导的2型糖尿病模型中对SGK-1的表达进行体内评估。
结果
25 mmol/L葡萄糖和EGF（10 ng/mL）分别增加了SGK-1 mRNA（分别为P < 0.005和P < 0.002）和蛋白（均为P < 0.02）表达。高糖和SGK-1过表达增加了NHE3 mRNA（P < 0.05）和EGFR磷酸化（P < 0.01），而PKI166可使其逆转。SGK-1过表达增加了PTC生长（P < 0.0001）、细胞周期进程（P < 0.001），并增加了NHE3 mRNA（P < 0.01），这些均被PKI166逆转。SGK-1过表达还可保护PTCs免受诱导的凋亡（P < 0.0001）。在体内证实了糖尿病中肾小管SGK-1 mRNA的上调。口服PKI166可使这种增加减少51%。在PTCs中未检测到EGF蛋白，提示高糖对EGFR的磷酸化以及SGK-1的下游诱导作用。
结论
高糖对PTC增殖、凋亡减少以及NHE3 mRNA水平增加的影响是由EGFR依赖性上调SGK-1介导的。
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