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Br J Pharmacol. 2014 Feb;171(4):879-87. doi: 10.1111/bph.12418.

Midkine in nephrogenesis, hypertension and kidney diseases.

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Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.


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.


This article is part of a themed section on Midkine. To view the other articles in this section visit


acute kidney injury (AKI); chronic kidney injury (CKD); hypertension; inflammation; midkine; nephrogenesis; renin-angiotensin system (RAS)

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