title: Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Honda
authors.affiliation: 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.). tshishid@med.id.yamagata-u.ac.jp.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.affiliation: 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.).
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: 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.).
authors.forename: Tetsu
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: 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.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Netsu
authors.affiliation: 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.).
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kinoshita
authors.affiliation: 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.).
authors.forename: Taro
authors.initials: T
authors.lastname: Narumi
authors.affiliation: 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.).
authors.forename: Shinpei
authors.initials: S
authors.lastname: Kadowaki
authors.affiliation: 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.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishiyama
authors.affiliation: 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.).
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: 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.).
authors.forename: Takanori
authors.initials: T
authors.lastname: Arimoto
authors.affiliation: 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.).
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: 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.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishida
authors.affiliation: 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.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.affiliation: 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.).
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.affiliation: 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.).
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000188:drug therapy / Q000503:physiopathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000078792:Midkine; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009392:Nephrectomy; D010766:Phosphorylation / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000503:physiopathology; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D016207:Cytokines; D011799:Quinazolines; D000078792:Midkine; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: cardiomegaly; hypertrophy, left ventricular; midkine; nephrectomy; receptor, epidermal growth factor; renal insufficiency, chronic