Midkine (MK; K; gene abbreviation, Mdk: mus musculus, MDK: homo sapiens) is a multifunctional
heparin-binding
growth factor that regulates cell growth, survival and migration as well as anti-apoptotic activity in nephrogenesis and development. Proximal tubular epithelial cells are the main sites of MK expression in the kidneys. The pathophysiological roles of MK are diverse, ranging from the development of
acute kidney injury (AKI) to the progression of
chronic kidney disease, often accompanied by
hypertension, renal ischaemia and
diabetic nephropathy. The obvious
hypertension that develops in Mdk(+/+) mouse models of renal ablation compared with Mdk(-/-) mice eventually leads to progressive
renal failure, such as glomerular
sclerosis and tubulointerstitial damage associated with elevated plasma
angiotensin (Ang) II levels. MK is also induced in the lung endothelium by oxidative stress and subsequently up-regulated by ACE, which hydrolyzes Ang II to induce further oxidative stress, thus accelerating MK generation; this leads to a vicious cycle of positive feedback in the MK-Ang II pathway. Kidney-lung interactions involving positive feedback between the renin-angiotensin system and MK might partly account for the pathogenesis of
hypertension and kidney damage. MK is also involved in the pathogenesis of AKI and
diabetic nephropathy through the recruitment of inflammatory cells. In contrast, MK plays a protective role against crescentic
glomerulonephritis, by down-regulating
plasminogen activator inhibitor-1. These diverse actions of MK might open up new avenues for targeted approaches to treating
hypertension and various renal diseases.
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