Midkine in nephrogenesis, hypertension and kidney diseases

Abstract

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

Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1-TLR4 signaling in rat tubulo-epithelial cells

“…However, the mechanisms by which hypertension contributes to the progression of renal injury is not clear. In this study, we observed that AngII exposure resulted in significant up-regulation of TNFα and IL-1β in NRK52E cells after 6 h. Our results are consistent with those of previous studies which have shown that AngII infusion increases the production of PIC in rat kidneys [53][54][55]. Although previous studies have investigated the effects of AngII on kidneys, the upstream signaling mechanism are not well understood.…”

Transcriptome Analysis of Human Reninomas as an Approach to Understanding Juxtaglomerular Cell Biology

“…In agreement with this concept, the current study revealed no effect of either SPARC, SPARCL1 or MGE8 alone on (pro)renin synthesis by As4.1 cells. Additionally, ligands that are known to be involved in blood pressure regulation (NPPC, or natriuretic peptide precursor C), diabetic nephropathy (LGALS1 or galectin-1) 26 , nephrogenesis (MDK or midkine) 27 , renal fibrosis (WFDC2, or WAP four-disulfide core domain protein 2) 28 , and renal injury prevention (FSTL1, or follistatin-related protein 1) 29 also did not directly affect (pro)renin synthesis by As4.1 cells.…”

Psychrophilic proteases dramatically reduce single cell RNA-seq artifacts: A molecular atlas of kidney development

“…They were first divided into two subgroups. One of these represented early proximal tubule progenitor cells, expressing midkine, which is associated with the early proximal tubule (Sato and Sato, 2014), as well as Osr2, Lhx1 and Jag1, which are markers of early nephron developmental stage cells, preceding the proximal tubule (Fig. S2).…”