Multiple pathophysiological roles of midkine in human disease.

Midkine (MK) is a low molecular-weight protein that was first identified as the product of a retinoic acid-responsive gene involved in embryonic development. Recent studies have indicated that MK levels are related to various diseases, including cardiovascular disease (CVD), renal disease and autoimmune disease. MK is a growth factor involved in multiple pathophysiological processes, such as inflammation, the repair of damaged tissues and cancer. The pathophysiological roles of MK are diverse. MK enhances the recruitment and migration of inflammatory cells upon inflammation directly and also through induction of chemokines, and contributes to tissue damage. In lung endothelial cells, oxidative stress increased the expression of MK, which induced angiotensin-converting enzyme (ACE) expression and the consequent conversion from Ang I to Ang II, leading to further oxidative stress. MK inhibited cholesterol efflux from macrophages by reducing ATP-binding cassette transporter A1 (ABCA1) expression, which is involved in lipid metabolism, suggesting that MK is an important positive factor involved in inflammation, oxidative stress and lipid metabolism. Furthermore, MK can regulate the expansion, differentiation and activation of T cells as well as B-cell survival; mediate angiogenic and antibacterial activity; and possess anti-apoptotic activity. In this paper, we summarize the pathophysiological roles of MK in human disease.