Honda Yuki, Shishido Tetsuro, Takahashi Tetsuya, Watanabe Tetsu, Netsu Shunsuke, Kinoshita Daisuke, Narumi Taro, Kadowaki Shinpei, Nishiyama Satoshi, Takahashi Hiroki, Arimoto Takanori, Miyamoto Takuya, Kishida Satoshi, Kadomatsu Kenji, Takeishi Yasuchika, Kubota Isao
From the Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan (Y.H., T.S., T.T., T.W., S.N., D.K., T.N., S.K., S.N., H.T., T.A., T.M., I.K.); Department of Biochemistry, Nagoya University Graduate School of Medicine, Aichi, Japan (S.K., K.K.); and Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan (Y.T.).
Hypertension. 2016 May;67(5):857-65. doi: 10.1161/HYPERTENSIONAHA.115.06922. Epub 2016 Mar 14.
In chronic kidney disease, activation of the epidermal growth factor receptor (EGFR) leads to cardiac hypertrophy, which affects morbidity and mortality. In patients with renal insufficiency and heart failure, the expression of midkine, a heparin-binding growth factor, is increased. Therefore, we investigated the association between midkine and EGFR in the induction of cardiac hypertrophy and dysfunction in chronic kidney disease. We performed subtotal nephrectomies in midkine-knockout mice and wild-type mice. We found that subtotal nephrectomy-induced cardiac hypertrophy and phosphorylation of extracellular signal-regulated kinase 1/2 and AKT were attenuated in midkine-knockout mice compared with wild-type mice. An antiphosphotyrosine receptor antibody array was used to demonstrate that EGFR phosphorylation in the heart was also lower in midkine-knockout mice than in wild-type mice. Midkine induced EGFR, extracellular signal-regulated kinase 1/2, and AKT phosphorylation and led to hypertrophy in neonatal rat cardiomyocytes. Pretreatment with EGFR inhibitors or EGFR silencing suppressed midkine-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 and AKT, induction of fetal cardiac gene expression, and hypertrophy in cardiomyocytes. To confirm the association between midkine and EGFR in vivo, mice subjected to subtotal nephrectomy were treated with the EGFR inhibitor gefitinib. Gefitinib treatment attenuated subtotal nephrectomy-induced cardiac hypertrophy. These results indicate that midkine might be a key mediator of cardiorenal interactions through EGFR activation, which plays a crucial role in cardiac hypertrophy in chronic kidney disease.
在慢性肾脏病中，表皮生长因子受体（EGFR）的激活会导致心脏肥大，进而影响发病率和死亡率。在肾功能不全和心力衰竭患者中，一种肝素结合生长因子——中期因子的表达会增加。因此，我们研究了中期因子与EGFR在慢性肾脏病诱导心脏肥大和功能障碍中的关联。我们对中期因子基因敲除小鼠和野生型小鼠进行了肾大部切除术。我们发现，与野生型小鼠相比，肾大部切除术诱导的心脏肥大以及细胞外信号调节激酶1/2和AKT的磷酸化在中期因子基因敲除小鼠中有所减弱。使用抗磷酸酪氨酸受体抗体阵列来证明，中期因子基因敲除小鼠心脏中的EGFR磷酸化也低于野生型小鼠。中期因子可诱导EGFR、细胞外信号调节激酶1/2和AKT磷酸化，并导致新生大鼠心肌细胞肥大。用EGFR抑制剂预处理或使EGFR沉默可抑制中期因子刺激的细胞外信号调节激酶1/2和AKT磷酸化、胎儿心脏基因表达的诱导以及心肌细胞肥大。为了在体内证实中期因子与EGFR之间的关联，对接受肾大部切除术的小鼠用EGFR抑制剂吉非替尼进行治疗。吉非替尼治疗减轻了肾大部切除术诱导的心脏肥大。这些结果表明，中期因子可能是通过EGFR激活介导心肾相互作用的关键介质，而EGFR激活在慢性肾脏病的心脏肥大中起关键作用。
