Midkine, a heparin-binding protein, is increased in the diabetic mouse kidney postmenopause

Diamond‐Stanic, Maggie; Romero-Aleshire, Melissa Jill; Hoyer, Patricia B.; Greer, Kevin; Hoying, James B.; Brooks, Heddwen L.

doi:10.1152/ajprenal.00249.2010

Cited by 17 publications

(15 citation statements)

References 48 publications

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“…Persistent hyperglycaemia is known to induce severe endothelial dysfunction, oxidative stress and inflammation, leading to changes in renal morphology and haemodynamics. These processes involve various chemokines, including Ang II, NO, TGF‐β, IL‐1β, plasminogen activator inhibitor‐1 (PAI‐1) and MCP‐1 (Diamond‐Stanic et al ., ). Diabetic nephropathy thus warrants a multidisciplinary approach to elucidate the underlying molecular mechanisms.…”

Section: Mk and Diabetic Nephropathymentioning

confidence: 97%

“…Macrophage recruitment activated by MK in TECs through MCP‐1 induction at the early stage of diabetic nephropathy eventually results in tubulointerstitial injury (Kosugi et al ., ). In addition, menopause aggravates diabetic nephropathy and MK is up‐regulated (demonstrated using DNA microarrays; Diamond‐Stanic et al ., ). Endothelial NO synthase expression is strikingly decreased in this model (Figure ).…”

Section: Mk and Diabetic Nephropathymentioning

confidence: 97%

“…Diabetes in a mouse model of menopause treated with 4-vinylcyclohexene diepoxide was induced using STZ and then post-menopausal changes in gene expression in the diabetic kidney were assessed using DNA microarrays. Real-time PCR, for confirmation, randomly identified the Mdk gene and the immediate early response gene 3 (Diamond-Stanic et al, 2011).…”

Section: Figurementioning

confidence: 99%

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Midkine in nephrogenesis, hypertension and kidney diseases

Sato

2014

British J Pharmacology

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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

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Section: Mk and Diabetic Nephropathymentioning

confidence: 97%

Section: Mk and Diabetic Nephropathymentioning

confidence: 97%

Section: Figurementioning

confidence: 99%

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Midkine in nephrogenesis, hypertension and kidney diseases

Sato

2014

British J Pharmacology

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“…The incidence of kidney disease in women is lower than in men in the same age group, and the loss of ovarian hormones is thought to accelerate kidney damage. The VCD model of menopause has been used to examine the impact of menopause on the onset and progression of diabetic kidney disease and the metabolic syndrome (4,9). First, to examine the impact of menopause on the progression of diabetic kidney disease, we used streptozotocin (STZ) (model of Type 1 diabetes, hyperglycemia) to induce diabetes in VCD-treated animals during perimenopause or 2 wk after the onset of menopause.…”

Section: Postmenopausal Diabetic Kidney Disease and The Metabolic Synmentioning

confidence: 99%

The VCD Mouse Model of Menopause and Perimenopause for the Study of Sex Differences in Cardiovascular Disease and the Metabolic Syndrome

2016

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In females, menopause, the cessation of menstrual cycling, is associated with an increase in risk for several diseases such as cardiovascular disease, osteoporosis, diabetes, the metabolic syndrome, and ovarian cancer. The majority of women enter menopause via a gradual reduction of ovarian function over several years (perimenopause) and retain residual ovarian tissue. The VCD mouse model of menopause (ovarian failure in rodents) is a follicle-deplete, ovary-intact animal that more closely approximates the natural human progression through perimenopause and into the postmenopausal stage of life. In this review, we present the physiological parameters of how to use the VCD model and explore the VCD model and its application into the study of postmenopausal disease mechanisms, focusing on recent murine studies of diabetic kidney disease, the metabolic syndrome, and hypertension.

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“…We also found a fracture-induced increase in Mdk serum levels, which was attenuated by the Mdk-Ab. Because it was shown previously that Mdk is an estrogen-responsive gene and that Mdk expression is enhanced in the murine postmenopausal diabetic kidney [ 17 ], we hypothesized that Mdk may also be involved in the pathogenesis of compromised bone healing after estrogen withdrawal. The present study demonstrated that Mdk serum levels were significantly increased after fracture, particularly in osteoporotic mice, and that treatment with an Mdk-Ab abolished the negative influence of ovariectomy (OVX) on bone healing.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Midkine Augments Osteoporotic Fracture Healing

Haffner‐Luntzer¹,

Kemmler²,

Heidler³

et al. 2016

PLoS ONE

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The heparin-binding growth and differentiation factor midkine (Mdk) is proposed to negatively regulate osteoblast activity and bone formation in the adult skeleton. As Mdk-deficient mice were protected from ovariectomy (OVX)-induced bone loss, this factor may also play a role in the pathogenesis of postmenopausal osteoporosis. We have previously demonstrated that Mdk negatively influences bone regeneration during fracture healing. Here, we investigated whether the inhibition of Mdk using an Mdk-antibody (Mdk-Ab) improves compromised bone healing in osteoporotic OVX-mice. Using a standardized femur osteotomy model, we demonstrated that Mdk serum levels were significantly enhanced after fracture in both non-OVX and OVX-mice, however, the increase was considerably greater in osteoporotic mice. Systemic treatment with the Mdk-Ab significantly improved bone healing in osteoporotic mice by increasing bone formation in the fracture callus. On the molecular level, we demonstrated that the OVX-induced reduction of the osteoanabolic beta-catenin signaling in the bony callus was abolished by Mdk-Ab treatment. Furthermore, the injection of the Mdk-Ab increased trabecular bone mass in the skeleton of the osteoporotic mice. These results implicate that antagonizing Mdk may be useful for the therapy of osteoporosis and osteoporotic fracture-healing complications.

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Midkine, a heparin-binding protein, is increased in the diabetic mouse kidney postmenopause

Abstract: Diamond-Stanic MK, Romero-Aleshire MJ, Hoyer PB, Greer K, Hoying JB, Brooks HL. Midkine, a heparin-binding protein, is increased in the diabetic mouse kidney postmenopause. Am J Physiol

Cited by 17 publications

References 48 publications

Midkine in nephrogenesis, hypertension and kidney diseases

Midkine in nephrogenesis, hypertension and kidney diseases

The VCD Mouse Model of Menopause and Perimenopause for the Study of Sex Differences in Cardiovascular Disease and the Metabolic Syndrome

Inhibition of Midkine Augments Osteoporotic Fracture Healing

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