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- Jaminon, AMG, et al.
(författare)
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Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 6586-
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Tidskriftsartikel (refereegranskat)abstract
- Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0–1312]) compared to patients carrying a T allele (median 0 [range 0–966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.
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- Laget, J, et al.
(författare)
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Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study
- 2023
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated whether senescence and NRF2 pathways may serve as drivers of uremia-induced VC using three complementary approaches: a novel model of induced VC in 5/6-nephrectomized rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD patients with established medial calcification; and vascular smooth muscle cells (VSMCs) incubated with uremic serum. Expression of p16Ink4a and p21Cip1, as well as γ-H2A-positive cells, confirmed increased senescent cell burden at the site of calcium deposits in aortic sections in rats, and was similarly observed in calcified epigastric arteries from CKD patients through increased p16Ink4a expression. However, uremic serum-induced VSMC calcification was not accompanied by senescence. Expression of NRF2 and downstream genes, Nqo1 and Sod1, was associated with calcification in uremic rats, while no difference was observed between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven VC was associated with depleted NRF2 expression. Together, our data strengthen the importance of senescence and NRF2 pathways as potential therapeutic options to combat VC in CKD.
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- Liu, C, et al.
(författare)
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Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease
- 2019
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Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 317:5, s. F1122-F1131
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Tidskriftsartikel (refereegranskat)abstract
- Advanced chronic kidney disease (CKD) is characterized by a premature aging phenotype of multifactorial origin. Mitochondrial dysfunction is prevalent in CKD and has been proposed as a major contributor to poor muscle function. Although the mitochondria-derived peptides (MDPs) humanin and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis, and glucose control, the implications of MDP in CKD are unknown. We investigated humanin and MOTS-c protein expression in skeletal muscle and serum levels in CKD at stage 5 (glomerular filtration rate: <15 ml/min) patients and age-matched controls with normal renal function. Whereas circulating levels of humanin were increased in CKD, local muscle expression was reduced. In contrast, MOTS-c levels were reduced in both skeletal muscle and serum in CKD. Humanin in serum correlated positively to circulating TNF levels. Reduced MDP levels in skeletal muscle were associated with lower mitochondrial density and evidence of oxidative stress. These results indicate a differential regulation of MDPs in CKD and suggest an alternative site for humanin production than skeletal muscle in the uremic milieu. MDP levels were linked to systemic inflammation and evidence of oxidative stress in the muscle, two hallmark features of premature aging and uremia.
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