Tag Archives: Iron

Renal Iron Handling In Health and Disease

Invitation to submit research and review articles related to Renal Iron Handling in Health and Disease.

While iron is a pre-requisite for life, it also initiates a cascade of pathological events that lead to parenchymal damage and activation of immune cells. Iron-dependent regulated cell death, namely ferroptosis, potentiates kidney injury and ironically, delivery of iron (or iron-loaded macrophages) to the kidney reduces the severity of the disease. Clearly, this represents our incomplete understanding iron metabolism in kidney health and pathology.


              We invite investigators to contribute original research articles as well as review articles that will aid in the understanding of iron metabolism and trafficking in the initiation and outcomes of kidney injury and chronic kidney disease.

Potential topics include, but are not limited to:

• Characterization and determination of the role of the kidney in iron trafficking and metabolism
• Effects of disorders of systemic iron metabolism (e.g. iron deficiency and iron overload) on the kidney, including new techniques to measure iron content (free or protein-bound) in tissue, plasma and cells
– Iron homeostasis in kidney disease (proteinuria, glomerulopathy and chronic kidney disease)
• Mechanism of iron-mediated kidney injury;
• Modulation of iron and hepcidin levels as therapeutic strategies to overcome injury and/or promote recovery 


Please use the following link to access the submission page

https://www.frontiersin.org/research-topics/11684/renal-iron-handling-in-health-and-disease

Direct targeting of iron absorption in the gut- the future of iron-overload therapy?

CRITICAL READ

In a recent article in Nanomedicine, Yingfang Fan and colleagues proposed a new approach to the treatment of iron overload (3). They used pH-sensitive gelatin nanoparticles for oral delivery of siRNA targeting divalent metal transport 1 (DMT1). They found that they could decrease DMT1 expression in the mouse gut, and consequently absorption of Fe59. This approach, the authors argued, presented advantages over the use of iron chelators, which lack specificity. This is an interesting new angle in the treatment of iron overload, although the authors have yet to test the efficacy of their method in hemochromatosis mice. What is the translational potential of this approach?.  Well, the oral delivery through pH-sensitive nanoparticles appears to ensure specificity for gut DMT1. Indeed the authors reported that their nanoparticles did not affect DMT1 expression in other tissues. 

One pertinent question is the effect of DMT1 blockade on iron levels, and consequently on the HIF-2α/FPN axis that regulates intestinal iron absorption. This is a space to watch………………

Contributed by Prof Samira Lakhal-Littleton, Department of Physiology, Anatomy & Genetics

University of Oxford

Postdoctoral Research Fellow in Iron Biology – IRSD Toulouse, France

A postdoctoral research fellow position is available for 3 years in the Delphine Meynard research group (http://en.irsd.fr/team-4-genetics-and-regulation-of-iron-metabolism.html).  We are part of the Digestive Health Research Institute (IRSD) in Toulouse in France. Toulouse is a dynamic research area located in south of France that comprises many internationally recognized laboratories and gives access to a network of high-level skills research platforms in life sciences (fundamental biology, agronomy, environment, health) making possible almost all research projects.

The Digestive Health Research Institute accredited by INSERM, INRA, ENVT and Toulouse University, is internationally recognized and offerins a productive scientific environment centered on basic and clinical research to understand and treat diseases of the intestine and the liver. IRSD brings together a total of >80 researchers, professors, technicians, students and post-docs of different nationalities.

Our research focuses on iron metabolism and its disturbance in human diseases. Our lab is a dynamic team of scientists, MD, graduate students, and technicians. Our main goal is to characterize the regulation of iron homeostasis at the cellular and molecular levels and to develop new therapeutic strategies for the treatment of iron related disorders. The postdoctoral project will specifically address the role of proteases in the regulation of iron homeostasis and develop new strategies to target those proteases. The postdoctoral fellow will use several approaches including molecular and cellular biology, animal models, and biochemistry but also techniques related to proteases such as enzymatic activity assay, activity based probes, and in situ zymography.

Applicants for this position must have a Ph.D. in the biochemical sciences. A suitable candidate will have a proven track record of research accomplishments including first author publications in international peer-reviewed journals and excellent experience in: molecular and cellular biology, biochemistry, mouse models. Skills with proteases would be appreciable. In addition, excellent communication/interpersonal skills are required.

Please email a cover letter, CV, and two letters of support from former mentors or collaborators (including their contact information) to Delphine Meynard: delphine.meynard@inserm.fr

Matriptase-2 Deficiency Protects From Obesity by Modulating Iron Homeostasis

Folgueras AR, Freitas-Rodríguez S, Ramsay AJ, Garabaya C, Rodríguez F, Velasco G, López-Otín C. Nat Commun. 2018 Apr 10;9(1):1350 PDF

Commentary by Dr Gautam Rishi and Prof Nathan Subramaniam Liver Disease and Iron Disorders Research Group, Queensland University of Technology, Brisbane.

Iron dysfunction is associated with many clinical conditions including neurodegenerative disorders, cancers, the anemia associated with chronic disease, and many iron disorders. Several studies have also linked disturbed iron regulation with metabolic disorders including obesity; however in most cases it is linked to iron deficiency, with chronic inflammation identified as a possible cause. The iron regulatory hormone hepcidin is regulated by a number of proteins and various stimuli. Matriptase-2, encoded by TMPRSS6, is thought to be a repressor of hepcidin expression through its cleavage of the positive regulator, hemojuvelin (encoded by HJV). A deficiency of matriptase-2 in humans is associated with a form of anemia termed iron-refractory iron deficiency anemia (IRIDA).

This study by Folgueras et al, from the laboratory of Prof Carlos Lopez-Otin, demonstrates that mice with deficiency of matriptase-2 are protected from obesity induced by a high-fat diet. The authors demonstrate, and ascribe this protective effect to the increased breakdown of fat/lipids in matriptase-2 deficient mice resulting in decreased fat deposition. Surprisingly, the authors observed decreased levels of the “hunger hormone” leptin and a concomitant increase in food intake in matriptase-2 knockout mice which however showed decreased weight gain. Matriptase-2 knockout mice fed a high fat diet also had decreased liver steatosis and improved glucose tolerance. Decreasing hepcidin expression in matriptase-2 knockout mice through use of a neutralizing antibody against HJV reversed these effects. In summary these exciting studies demonstrate an important role for hepcidin and thus iron regulation in lipid homeostasis and function of adipocytes, opening new avenues in the fight against obesity.

 

Deferiprone – The first approved orally active iron chelator by Bob Hider

Bob Hider

Bob Hider
Institute of Pharmaceutical Science
King’s College London

Patients with chronic refractory anemias receiving regular blood transfusions accumulate iron with potential damage to the liver, endocrine system and heart. The body has no mechanism for the active excretion of iron so each unit of blood adds 200-250mg iron to the body’s iron burden. Initially this excess iron is stored in the macrophages of the reticuloendothelial system but as the load increases and the saturation of plasma transferrin reaches 100% or more, the excess iron is deposited into the parenchymal cells of these organs. Thalassemia major (TM), in which there is an inherited failure to synthesise the beta globin chain of haemoglobin, is the most common transfusion dependent iron loading disease worldwide, and in which most trials of iron chelation drugs have been performed. Moreover in TM there is inappropriately increased absorption of dietary iron due to a low plasma hepcidin concentration. Without iron chelation therapy, mean survival from birth in TM was 12-17 years (Borgna-Pignatti, 2004), death occurring mainly from cardiac failure or arrhythmia. In 1976 Propper, Nathan and colleagues introduced the first effective iron chelation therapy, daily subcutaneous infusions of deferoxamine (DFO) (Propper, Shurin & Nathan, 1976). Subcutaneous infusions of DFO improved the life expectancy of those who could comply with the demanding routine of self -administered infusions over 12 hours for at least 5 days each week. Failure of compliance, side effects, hypersensitivity and the high cost of the drug, pump, needles and tubing precluded most of the worlds TM patients from receiving adequate chelation therapy and they continued to die prematurely (Modell et al, 2000). The need for an orally active, iron chelating drug was widely recognised and a large number of potential compounds were tested in cell cultures and in animals. Many chemists were searching for such molecules including Ray Bergeron, Bob Grady, Arthur Martell, Colin Pitt, Prem Ponka and Ken Raymond.

In 1977 I spent a sabbatical period in the Department of Biochemistry, Berkeley with Professor J. B. Neilands. Joe Neilands was the father figure in the field of siderophores (powerful iron chelators secreted by many bacteria and fungi) and had identified both the first hydroxamate – and first catechol-based siderophore. While working with the Neilands group, I became aware of studies by Ken Raymond in the Chemistry Department at Berkeley, some of which were directed at designing orally active iron chelators for the treatment of thalassemia. His candidates were modelled on catechol – containing siderophores. Based on my experience with membrane permeability, I realised that it was unlikely that any of Raymond’s candidate molecules would be sufficiently highly orally active, to be effective in the treatment of TM.Screen Shot 2018-04-26 at 12.34.48 PM

After returning to London, I identified hydroxypyridinones as possible substitutes for the catechol moiety in Raymond’s compounds, the major reason being that the resulting iron complexes would possess no net charge, in contrast to the 3 charge, typical of catechol siderophore iron complexes. Neutral molecules permeate biological membranes much more readily than charged molecules. At the time there was little work reported on hydroxypyridinones and no iron chelation data was available.        I approached the British Technology Group (BTG) for funding and they provided a grant which was sufficient to undertake some preliminary experiments. George Kontoghiorghes was appointed as a PhD student and started to study hydroxypyridinones and hydroxypyrones. Many of these compounds were found to bind iron tightly and relatively selectively. Some of them were found to facilitate the movement of iron through cell membranes. With continued funding from BTG we collaborated with Ernest Huehns and John Porter (UCL) in order to test six compounds for oral activity in mice. We discovered that the 3-hydroxypyridin-4-one (L1) possessed extremely high oral bioavailability, leading to efficient iron excretion. (Hider, Kontoghiorghes and Silver, 1982). The UCL/Essex group, then synthesised a range of 3-hydroxypyridin-4-ones to undertake a structure/activity study (Porter et al, 1988) and to initiate preliminary toxicity investigations. (Porter et al, 1991)

In 1986 there was a Ciba-Geigy Funded Meeting where the general opinion prevailed that the chance of finding a drug which is both active orally and not toxic when administered at 1g dose per day was extremely low. Several compounds had been identified which both bound iron tightly and entered cells rapidly, but without exception they were found to be toxic. The take away message was that a nontoxic oral iron chelator may never be identified. However the following year there was a “Workshop on the Development of Oral Iron Chelating Agents” in Herakleion, Crete which was sponsored both by Ciba-Geigy and BTG. More optimism was expressed at this meeting in presentations by Chaim Hershko (Diethyl HBED), Gary Brittenham (PIH derivatives) and George Kontoghiorghes and myself (Hydroxypyridinones) – may be the identification of a relatively nontoxic orally active iron chelator would be possible.

Back in London there was heated discussion as to whether or not we should prepare 1,2-dimethyl 3-hydroxypyridin-4-one (L1, CP20) for clinical studies or wait until we had completed investigation of the 3-hydroxypyridin-4-one analogues, thereby enabling us to select the most efficient, least toxic chelator. George Kontoghiorghes wanted to concentrate on L1, and to introduce it into clinical studies as quickly as possible. The rest of the UCL/Essex group considered this to be premature. As a result, Kontoghiorghes approached Victor Hoffbrand who at The Royal Free Hospital (RFH) was faced with many referred TM patients who had failed subcutaneous DFO therapy and were at risk of dying. After further animal studies, clinical trials began at the RFH in 1987 with L1 (subsequently named deferiprone).(Kontoghiorges et al, 1987) Thus deferiprone became the first orally active iron chelator to be successfully used in man.

There have been many controversies and important milestones centred on the use of deferiprone since 1987. I will mention two important developments that have occurred over this period.

The onset of the successful monitoring of iron in myocardial tissue by Anderson and Pennell (Anderson et al, 2004; Pennell et al, 2006) has led to the identification of deferiprone as being the most efficient chelator to remove iron from the heart. (Pennell et al, 2013). The mode of action is probably as indicated in figure 1, that is the noncharged nature of both the ligand and the iron complex permit both species to penetrate membranes by nonfacilated diffusion; ie the precise design feature which led to the identification of hydroxypyridinones in 1979-80.

There is now increasing evidence that elevated levels of iron in certain brain regions are associated with symptoms of neurodegeneration. (Crichton,Ward and Hider,2017). Currently a Phase 2 clinical trial based on the application of deferiprone to remove inappropriately accumulated brain iron is taking place in many European centres. Devos et al, 2014)

It is surprising to me that deferiprone, which is such a small molecule, possesses this considerable potential as a therapeutic agent.

References

Anderson, U., Westwood, M.A., et al. Brit. J. Haematol. 127 (2004) 348.

  1. Borgna-Pignatti, C., Rugolotto, S., et al. Haematologica 89 (204) 1187.
  2. Crichton, R., Ward, R., Hider R.C. Metal Chelation in Medicine, Royal Soc. Chem. (2017).
  3. Devos, A., et al. Antioxid. Redox Signaling 21 (2014) 195.
  4. Hider, R.C., Kontoghiorghes, G., Silver, J. UK Patent (1982) GB2118176.
  5. Kontoghiorghes, G., et al. The Lancet 329 (1987) 1294.
  6. Modell, B., Khan, M., Darlison, M. The Lancet 355 (2000) 2051.
  7. Pennell, D.J., Berdoukas, V., et al. Blood 107 (2006) 3738.
  8. Pennell, D.J., Udelson, E., et al. Circulation 128 (2013) 281.
  9. Porter, J.B., Gyparaki, M., et al. Blood 72 (1988) 1497.
  10. Porter, J.B., Hoyes, K.P., et al. Blood 78 (1991) 2727.
  11. Propper, R.D., Nathan, D.G., et al. Blood 48 (1976) 964.