Altered vitamin K biodistribution and metabolism in experimental and human chronic kidney disease

Kaesler, Nadine; Schreibing, Felix; Speer, Thimoteus; Puente-Secades, Sofia de la; Rapp, Nikolas; Drechsler, Christiane; Kabgani, Nazanin; Kuppe, Christoph; Jankowski, Vera; Schurgers, Leon J.; Kramann, Rafael; Floege, Jürgen

doi:10.1016/j.kint.2021.10.029

Cited by 26 publications

(33 citation statements)

References 48 publications

(71 reference statements)

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“…In mammals, vitamin K is a crucial coenzyme in the process of γ-carboxylation of amino acid residues, a rather rare posttranslational modification, which is required for the functioning of specific proteins necessary for blood coagulation as well as calcium and bone metabolism [ 41 ]. Furthermore, vitamin K metabolism is thought to play a critical role in cardiovascular calcification and associated complications, particularly in patients with chronic kidney disease [ 22 , 53 ]. A protein centrally involved in these vitamin K-dependent processes is VKOR, which is targeted by VKAs, certain derivatives of coumarins that are frequently used for anticoagulation in the clinic [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the identification of a safe, stable, and clinically applicable ferroptosis inhibitor for use in humans is an attractive therapeutic strategy for the treatment of AKI. A promising candidate in this respect is vitamin K1, a fatsoluble vitamin that has been used safely and reliably for decades in the prophylaxis of vitamin K deficiency bleeding in neonates [18,19] and for various ailments in adults, without showing toxicity even at very high doses [20][21][22].…”

Section: Cellular and Molecular Life Sciencesmentioning

confidence: 99%

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Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Kolbrink

Samson-Himmelstjerna

Messtorff

et al. 2022

Cell. Mol. Life Sci.

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Ferroptosis, a type of iron-dependent programmed cell death distinct from apoptosis, necroptosis, and other types of cell death, is characterized by lipid peroxidation, reactive oxygen species production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury. Therefore, ferroptosis has become a major focus for translational research. However, despite its involvement in pathological conditions, there are no pharmacologic inhibitors of ferroptosis in clinical use. In the context of drug repurposing, a strategy for identifying new uses for approved drugs outside the original medical application, we discovered that vitamin K1 is an efficient inhibitor of ferroptosis. Our findings are strengthened by the fact that the vitamin K antagonist phenprocoumon significantly exacerbated ferroptotic cell death in vitro and also massively worsened the course of acute kidney injury in vivo, which is of utmost clinical importance. We therefore assign vitamin K1 a novel role in preventing ferroptotic cell death in acute tubular necrosis during acute kidney injury. Since the safety, tolerability, pharmacokinetics, and pharmacodynamics of vitamin K1 formulations are well documented, this drug is primed for clinical application, and provides a new strategy for pharmacological control of ferroptosis and diseases associated with this mode of cell death.

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Section: Discussionmentioning

confidence: 99%

Section: Cellular and Molecular Life Sciencesmentioning

confidence: 99%

Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Kolbrink

Samson-Himmelstjerna

Messtorff

et al. 2022

Cell. Mol. Life Sci.

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“…The metabolome results also indicated that lycopene mainly enhanced vitamin K, betaalanine, glutathione, and propanoate metabolism in mouse kidneys. Among them, chronic kidney disease is associated with extensive cardiovascular calcification, partly related to vitamin K metabolism [40]. Common metabolic pathways in the kidneys include beta-alanine metabolism.…”

Section: Discussionmentioning

confidence: 99%

Lycopene-Loaded Bilosomes Ameliorate High-Fat Diet-Induced Chronic Nephritis in Mice through the TLR4/MyD88 Inflammatory Pathway

Liu

Wang

et al. 2022

Foods

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Chronic kidney disease caused by a high-fat diet (HFD)-induced metabolic syndrome has received widespread attention. Lycopene has a wide range of biological activities and can improve a variety of chronic diseases through anti-inflammatory effects. In this study, HFD-fed mice were used as a metabolic syndrome model to evaluate the protective effect of lycopene in a sustained-release vehicle (bilosomes) in the small intestine against renal injury and to determine whether the TLR4/MyD88 pathway and related metabolic pathways are involved in this process. The results showed that lycopene bilosomes alleviated HFD-induced kidney damage, as evidenced by lower serum urea nitrogen, creatinine, and uric acid levels. Histopathology studies showed that lycopene bilosomes attenuated HFD-induced tubular cell and glomerular injury. In addition, Elisa, RT-PCR, and Western blotting results showed that lycopene bilosomes also reduced the expression of inflammatory factors such as TLR4, MyD88, NF-kB, TNF-a, and IL-6 in mouse kidneys. The mechanism was to attenuate renal inflammatory response by inhibiting the TLR4/MyD88 inflammatory pathway. These findings suggested that lycopene can alleviate nephritis and metabolic disorders caused by HFD, inhibiting the TLR4/MyD88 inflammatory pathway and its downstream pro-inflammatory cytokines and further regulating the vitamin K metabolism, beta-alanine metabolism, and glutathione metabolism pathways to relieve chronic nephritis.

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“…The expressions of VK cycle enzymes were previously determined in different tissues of rats with adenine-induced CKD, and in general, the decreased recycling and utilization of VK was found [ 24 , 69 , 70 ]. To the best of our knowledge, this is the first study that measured the expression of genes involved in VK recycling at the bone level of uremic rats.…”

Section: Discussionmentioning

confidence: 99%

Vitamin K-Dependent Carboxylation of Osteocalcin in Bone—Ally or Adversary of Bone Mineral Status in Rats with Experimental Chronic Kidney Disease?

et al. 2022

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Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), and VK-dependent proteins: osteocalcin, undercarboxylated osteocalcin (Glu-OC), and undercarboxylated matrix Gla protein (ucMGP). The carboxylated osteocalcin (Gla-OC), Glu-OC, and the expression of genes involved in VK cycle were determined in bone. The obtained results were juxtaposed with the bone mineral status of rats with CKD. The obtained results suggest that the reduced VK1 level observed in CKD rats may be caused by the accelerated conversion of VK1 to the form of menaquinones. The bone tissue possesses all enzymes, enabling the conversion of VK1 to menaquinones and VK recycling. However, in the course of CKD with hyperparathyroidism, the intensified osteoblastogenesis causes the generation of immature osteoblasts with impaired mineralization. The particular clinical significance seems to have a finding that serum osteocalcin and Glu-OC, commonly used biomarkers of VK deficiency, could be inappropriate in CKD conditions, whereas Gla-OC synthesized in bone appears to have an adverse impact on bone mineral status in this model.

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Altered vitamin K biodistribution and metabolism in experimental and human chronic kidney disease

Cited by 26 publications

References 48 publications

Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Lycopene-Loaded Bilosomes Ameliorate High-Fat Diet-Induced Chronic Nephritis in Mice through the TLR4/MyD88 Inflammatory Pathway

Vitamin K-Dependent Carboxylation of Osteocalcin in Bone—Ally or Adversary of Bone Mineral Status in Rats with Experimental Chronic Kidney Disease?

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