MAGE genes in the kidney: identification of MAGED2 as upregulated during kidney injury and in stressed tubular cells

Valiño-Rivas, Lara; Cuarental, Leticia; Agustin, Mateo; Husi, Holger; Cannata‐Ortiz, Pablo; Sanz, Ana B.; Mischak, Harald; Ortíz, Alberto

doi:10.1093/ndt/gfy367

Cited by 20 publications

(16 citation statements)

References 41 publications

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“…In contrast, in Clock-mutant mice, Atp1b1 expression was low and blood pressure high [44]. The expression of both NCC and ATP1B1 is altered in kidney injury, potentially linking kidney injury to an altered expression of kidney circadian genes regulating blood pressure [45,46].…”

Section: Chronodisruption In Ckdmentioning

confidence: 96%

Chronodisruption: A Poorly Recognized Feature of CKD

Carriazo

Ramos

Sanz

et al. 2020

Toxins

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Multiple physiological variables change over time in a predictable and repetitive manner, guided by molecular clocks that respond to external and internal clues and are coordinated by a central clock. The kidney is the site of one of the most active peripheral clocks. Biological rhythms, of which the best known are circadian rhythms, are required for normal physiology of the kidneys and other organs. Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. While there is evidence that circadian rhythms may be altered in kidney disease and that altered circadian rhythms may accelerate chronic kidney disease (CKD) progression, there is no comprehensive review on chronodisruption and chronodisruptors in CKD and its manifestations. Indeed, the term chronodisruption has been rarely applied to CKD despite chronodisruptors being potential therapeutic targets in CKD patients. We now discuss evidence for chronodisruption in CKD and the impact of chronodisruption on CKD manifestations, identify potential chronodisruptors, some of them uremic toxins, and their therapeutic implications, and discuss current unanswered questions on this topic.

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Section: Chronodisruption In Ckdmentioning

confidence: 96%

Chronodisruption: A Poorly Recognized Feature of CKD

Carriazo

Ramos

Sanz

et al. 2020

Toxins

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“…PGC-1α is encoded by the PPARGC1A gene and belongs to the PGC-1 family, also composed of PGC-1β (encoded by PPARGC1B), which contributes to maintain basal mitochondrial function, and PRC (PGC-1-related coactivator, encoded by PPRC1), which appears to be restricted to regulating mitochondrial biogenesis in proliferating cells [24] ( Figure 1A). While there is abundant literature on PGC-1α and kidney disease, as discussed below, much less is known about the role of PGC-1β and PRC in kidney disease, despite the fact that transcriptomic studies have identified them as differentially expressed during experimental AKI [25][26][27] (Figure 1B). [28].…”

Section: Pgc-1α: a Regulator Of Mitochondrial Biogenesismentioning

confidence: 99%

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

et al. 2020

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Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

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“…Once TNFRSF12a/Fn14 was identified among the highest expressed TNFRSF genes in podocytes in vivo and the most upregulated in glomeruli in human MN, the impact of its ligand TWEAK on podocyte PLA2R expression was explored in mice and in cultured human podocytes and the impact of tacrolimus on TWEAK-induced PLA2R expression was explored in cultured human podocytes. Additionally, we queried a previously published in-house database that had evaluated by transcriptomics arrays the impact of 100 ng/mL TWEAK on gene expression in murine cultured proximal tubular epithelial MCT cells [18,19]. Specifically, we queried this database for the impact of TWEAK on the expression of genes identified by GWAS to be associated with MN [16].…”

Section: Data Mining and Overall Experimental Designmentioning

confidence: 99%

Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes

Cuarental

Valiño-Rivas

Mendonça

et al. 2020

JCM

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Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.

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MAGE genes in the kidney: identification of MAGED2 as upregulated during kidney injury and in stressed tubular cells

Cited by 20 publications

References 41 publications

Chronodisruption: A Poorly Recognized Feature of CKD

Chronodisruption: A Poorly Recognized Feature of CKD

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes

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