Magnesium treatment for vascular calcification

Our group has shown that magnesium prevents vascular calcification in vitro and in vivo. In bovine and human vascular smooth muscle cells (VSMC), Mg2+ effectively prevented high Pi-induced mineralization, as well as in mouse models of CKD. My team is currently working together with colleagues form the Amsterdam UMC and UMCG in the NIGRAM2+ consortium to translate our findings towards patients.

  • In Klotho knock-out mice, high Mg2+ intake prevented aortic calcification and molecular pathways involved in ECM remodeling and inflammation. (Kidney Int, 2020)
  • Magnesium was shown to prevent vascular calcification in vascular smooth muscle cell cultures. Our findings indicate that magnesium inhibits crystal formation and thereby prevents calcification. (Sci reports, 2018, Nephrol Dial Transplant 2020).
  • Literature research indicates that many studies support an association between serum magnesium and cardiovascular disease risk. A substantial body of in vitro and in vivo studies has identified a protective role for magnesium in vascular calcification. (Arterioscler Thromb Vasc Biol., 2017).
Research Research groups Magnesium in health and disease

About this research group

This research group examines the role of magnesium in health and disease. Our mission is to decipher the pathophysiological mechanisms of magnesoium-wasting tubulopathies by development of novel disease models and advanced methods to measure magnesium transport.

Research group leader

dr. Jeroen de Baaij
assistant professor

+31 (0)24 361 73 47
contact

Aims

Our research group has several aims.

  • In our view, the development of next-generation diagnostics and innovative functional methods to measure magnesium transport are essential.

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    Magnesium wasting tubulopathies

    In our view, the development of next-generation diagnostics and innovative functional methods to measure magnesium transport are essential to diagnose and to understand magnesium-wasting tubulopathies. We envision that patient-specific models are the future of pathophysiological research. Personalized drug screening to identify therapeutics that fit the needs of individual patients will become the new standard for treatment of rare diseases.


  • Dietary prevention of vascular calcification

    Cardiovascular complications are the main cause of death for patients with chronic kidney disease (CKD). Our research on magnesium in vascular calcification demonstrates that dietary interventions are an interesting approach to prevent cardiovascular disease in CKD. In our vision, better understanding of the influence of nutrients on vascular calcification is essential to develop dietary approaches to reduce cardiovascular mortality and morbidity in CKD. 


Discoveries

Several discoveries were made by our research group.

  • Our work resulted in the identification of novel magnesium-wasting tubulopathies caused by mutations in CNNM2, PCBD1, KCNJ16, RRAGD and TRPM7.

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    Magnesium wasting tubulopathies

    Our work resulted in the identification of novel magnesium-wasting tubulopathies caused by mutations in CNNM2, PCBD1, KCNJ16, RRAGD and TRPM7. By linking genetic screening to functional studies, we have provided insights into the mechanisms of magnesium reabsorption in the kidney.

    • We identified RRAGD mutations in a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy. Our findings demonstrate that an activation of mTOR signaling causes this novel disease phenotype, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function. (bioRxiv 2021)
    • KCNJ16 (Kir5.1) mutations were demonstrated to cause a novel hypokalemic tubulopathy.(J Am Soc Nephrol 2021) Moreover, HNF1B was shown to be the transcriptional regulator of the Kir5.1 K+ channel, explains why HNF1B patients suffer from hypomagnesemia and hypokalemia mimicking Gitelman syndrome. (Kidney Int 2017).
    • CNNM2 mutations were identified in patients with hypomagnesemia, intellectual disability and seizures. We showed in cell models, mice and zebrafish that CNNM2 is essential for the magnesium balance and brain development (PLOS Genetics 2014, Human Mutation 2021, Scientific Reports 2021).
    • Mutations in PCBD1 cause maturity-onset diabetes of the young and hypomagnesemia. PCBD1 was shown to be a co-factor of HNF1B and has an effect on the transcriptional regulation of magnesium reabsorption in the kidney (J Am Soc Nephrol 2013).

  • Hypomagnesemia in type 2 diabetes

    As 30% of all type 2 diabetics suffers from hypomagnesemia, we aim to effects of magnesium on lipid and glucose metabolism. Our work demonstrates that magnesium affects insulin sensitivity and lipid metabolism.

    • Magnesium deficiency abrogates HFD-induced obesity in mice through enhanced eWAT lipolysis and BAT activity. (Diabetologia, 2018).
    • Free fatty acid levels directly reduce the blood magnesium concentration, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. (Diabetelogia, 2019).
    • We determined that 30% of patients with diabetes mellitus type 2 has hypomagnesemia. Blood glucose and triglyceride levels were associated with blood magnesium concentration in a cohort of 400 patients. (Eur J Endocrinol Metab., 2017).

Jeroen de Baaij The rewards of multiple grants

Jeroen de Baaij obtained several personal grants this year. Here, he talks about his plans for the future and how these grants will enable him to perform great science.

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Jeroen de Baaij The rewards of multiple grants

Jeroen de Baaij from the department of Physiology (theme: Renal disorders) was awarded not one, but three personal grants in 2017, adding up to € 750,000. It not only allows him to continue the research into magnesium deficiencies he started as a PhD candidate but also to set up his own research team. Jeroen is excited that he can shift focus from a rare disease to issues that effect a larger population. It’s no wonder that both the Dutch kidney and diabetes foundations are supporting his research. Summing up, he was awarded the following personal grants in 2017: Veni Grant from the Netherlands Organization for Scientific Research (NWO), a Junior Kolff Fellowship from the Dutch Kidney Foundation and a Junior Fellowship from the Dutch Diabetes Research Foundation. Jeroen is also part of a consortium that was awarded a grant.

Q1 What are you going to research with these funds?

“My research will build on what I studied as a PhD candidate. I looked at the genetic origin of disease in patients with magnesium disturbances. Renal magnesium wasting is often the cause of hypomagnesemia in patients. Magnesium deficiency can cause such things as fatigue, generalized weakness, muscle cramps and abnormal heart rhythms. As a PhD candidate I looked at rare diseases and was so able to concentrate on one defect. Now I turn my attention to a larger population.
 
Magnesium deficiency, for example, is also connected to diabetes. One in three diabetic patients has a magnesium deficiency. What is the correlation: does diabetes cause the magnesium deficiency or does magnesium deficiency contribute to the development of diabetes?
 
My current research project 'The magnesium journey through the renal cell: how to get out?' will examine the cells that transport magnesium in the kidney. For fifteen years, it’s been known how magnesium enters these kidney cells, but the mechanism of subsequent extrusion to the blood compartment remains elusive.”

Q2 The received funding allows you to set up your own team. Such a large team is happening sooner than it might otherwise have. Does leading a team make you nervous?

“No, not at all. I get great energy from a team. As a starting postdoc, I also had the funds to get assistance. I got the chance to train people and I really enjoy supervising other researchers. Watching them grow is rewarding. It doesn’t put pressure on me but I’m aware that to continue with a team I’ll need to keep the funds coming in. There’s a time pressure. You cannot slack on finding funding or on getting research results. For example, you can only apply for a Veni, Vidi or Vici grant within a certain amount of years after your PhD. With the current grants I can move forward for a few years, but soon I’ll have to start applying for new grants again.”

Q3 I’m guessing, having to apply for these grants takes a lot of time. Do you think it’s a lot of precious time that’s taken away from research?

“I’ve been very fortunate to have received a number of grants. I can imagine if you’ve spent a lot of time applying but not receiving anything, that it can be frustrating. I do feel, though, that there’s value to applying for grants. It helps shape your ideas. You can easily get distracted by all the small issues and possible paths that a project can take. Grant writing forces you to make clear decisions.
 
There is, however, a long waiting process which can be tiresome. I might write a proposal in January and not hear until December if I got the grant. In between there are lots of steps that also demand your time and attention.”

Q4 You received two funds from a foundation. Did your research have to have a clear outcome for patients to be applicable for these grants?

“A foundation does want the benefits for their target group to be clear. And that’s fair enough. People have spent lots of time gathering funds for these specific patients. The role of the patient is more important for foundations. The Veni grant, for example, focuses much more on pure scientific issues and academic talent. I will continue in research as long as the questions are interesting and I can get to the next step
 
But it’s wrong to think that foundations are specifically looking for a new treatment. When applying for these grants I concentrated more on the patients. For one application I even consulted with some patients and took their comments on board. When I had the chance to talk to patients, I realized that for them, finding a treatment is not all they want from research. For them understanding what is happening and why it’s happening is also important. Simply knowing can make a huge difference to them.”

Q5 Was it always clear to you that you wanted to help patients by doing research?

“To be honest, when I began studying Biology, I thought the last thing I’d be doing was research. I guess I had a naïve image of researcher: a pipette in hand, tucked away in a lab. But during my Master’s in France I realized it’s so much more. It’s about solving puzzles. It’s also about working together. Research can be a slow process but it’s also so rewarding.
 
I will continue in research as long as the questions are interesting and I can get to the next step. I’m really not sure where the questions will take me. We’ll see.”


Regulation of magnesium transport by TRPM6

Team