Abstract 11001: Growth Factor Midkine Deteriorates Cadiac Hypertrophy via Epidermal Growth Factor Receptor Signaling: A Novel Mediator of Cardio-Renal Interaction

Background: Midkine (MK), a 13-kDa heparin-binding growth factor, has shown to be up-regulated in injured renal tubule, and released into circulation. We recently reported that cardiac-specific overexpression of MK exacerbates cardiac hypertrophy in mice. However, it remains unknown by which mechanisms MK affects on heart. Although receptors for MK are thought to be receptor-type tyrosine kinase, specific receptor for MK has not been determined. Here we show that MK acts by activating the epidermal growth factor receptor (EGFR) and its downstream signaling and leads to cardiac hypertrophy. Methods and Results: MK phosphorylated EGFR (Tyr1068) on neonatal rat cardiomyocytes. MK also promoted phosphorylation of ERK1/2 and Akt, induced fetal cardiac gene expression, and led to cardiomyocyte hypertrophy. Pre-treatment with EGFR inhibitors attenuated MK-induced ERK1/2 and Akt phosphorylation, and induction of fetal cardiac gene, as well as cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. EGFR silencing by siRNA also attenuated MK-induced cardiomyocyte hypertrophy. Next, we examine whether the action of MK mediates EGFR transactivation using TAPI-2, a metalloproteinase inhibitor, to inhibit EGFR transactivation. Pre-treatment with TAPI-2 did not affect MK-induced elevated cardiac fetal gene activity and activation of EGFR, suggesting that MK may directly phosphorylated EGFR rather than mediating EGFR transactivation. For in vivo study, subtotal nephrectomy was created with MK systemic knockout (MK-KO) mice and littermate wild-type (WT) mice. Subtotal nephrectomy induced cardiac hypertrophy and poor survival rate in WT mice, whereas cardiac hypertrophy and survival rate was improved in MK-KO mice compared with WT mice. Conclusions: We demonstrated for the first time that EGFR signaling plays a crucial role in MK-induced cardiac hypertrophy, and MK is thought to be one of key molecule mediating cardio-renal interaction.