Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression

Liebisch, Marita; Bondeva, Tzvetanka; Franke, Sybille; Daniel, Christoph; Amann, Kerstin; Wolf, Günter

doi:10.1038/ki.2014.3

Cited by 21 publications

(26 citation statements)

References 68 publications

(108 reference statements)

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“…Previous work of our group showed that the expression of the nuclear inhibitor of protein phosphatase 1 (NIPP1) was significantly decreased in podocytes of diabetic db/db mice, and as well in vitro in murine podocytes treated with glycated BSA (AGE-BSA) [5]. Similar findings were observed in renal biopsy specimens from patients with DKD [5].…”

Section: Introductionsupporting

confidence: 72%

AGE-Induced Suppression of EZH2 Mediates Injury of Podocytes by Reducing H3K27me3

Liebisch

Wolf²

2020

Am J Nephrol

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Background: Chronic hyperglycemia, a pivotal feature of diabetes mellitus (DM), initiates the formation of advanced glycation end products (AGEs) and the dysregulation of epigenetic mechanisms, which may cause injury to renal podocytes, a central feature of diabetic kidney disease (DKD). Previous data of our group showed that AGEs significantly reduce the expression of NIPP1 (nuclear inhibitor of protein phosphatase 1) in podocytes in vitro as well as in human and murine DKD. NIPP1 was shown by others to interact with enhancer of zeste homolog 2 (EZH2), which catalyzes the repressive methylation of H3K27me3 on histone 3. Therefore, we hypothesized that AGEs can directly induce epigenetic changes in podocytes. Methods: We analyzed the relevance of AGEs on EZH2 expression and activity in a murine podocyte cell line. Cells were treated with 5 mg/mL glycated BSA for 24 h. To determine the meaning of EZH2 suppression, EZH2 activity was inhibited by incubating the cells with the pharmacological methyltransferase inhibitor 3-deazaneplanocin A; EZH2 expression was repressed with siRNA. mRNA expression was analyzed with real-time PCR, and protein expression with Western blot. EZH2 expression and level of H3K27 trimethylation in podocytes of diabetic db/db mice, a mouse model for type 2 DM, were analyzed using immunofluorescence. Results: Our data demonstrated that AGEs decrease EZH2 expression in podocytes and consequently reduce H3K27me3. This suppression of EZH2 mimicked the AGE effects and caused an upregulated expression of pathological factors that contribute to podocyte injury in DKD. In addition, analyses of db/db mice showed significantly reduced H3K27me3 and EZH2 expression in podocytes. Moreover, the suppression of NIPP1 and EZH2 showed similar effects regarding podocyte injury. Conclusions: Our studies provide a novel pathway how AGEs contribute to podocyte injury and the formation of the so-called metabolic memory in DKD.

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Section: Introductionsupporting

confidence: 72%

AGE-Induced Suppression of EZH2 Mediates Injury of Podocytes by Reducing H3K27me3

Liebisch

Wolf²

2020

Am J Nephrol

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“…This inhibition may be a potential therapeutic advantage because local renal proinflammatory processes are important for the development and progression of DN [8,9]. In addition, it has been shown that AGE-BSA activates proinflammatory pathways in other cell systems [22,23,24]. Although clinical studies have suggested that paricalcitol may have advantages over ‘classical' vitamin D3 [25,26], in our in vitro study, vitamin D3 and paricalcitol were equally effective in suppressing the NFκB activation (albeit in some experiments, e.g.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D3 Partly Antagonizes Advanced-Glycation Endproducts-Induced NFκB Activation in Mouse Podocytes

Rüster

Franke²,

Reuter³

et al. 2016

Nephron

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Background/Aims: We have previously shown that advanced glycation-endproducts (AGEs) induced NFκB activation in differentiated mouse podocytes. This NFκB activation may contribute to the progression of renal disease and mediation of fibrosis by various mechanisms. This study was undertaken to test whether this detrimental response may be reversed by vitamin D3 or its analogue paricalcitol. Methods: Differentiated mouse podocytes were challenged with glycated bovine serum albumin (AGE-BSA), or non-glycated control BSA (in the presence or absence of various concentrations of vitamin D3 (decostriol, 1α,25-dihydroxyvitamin D3)) or its active analog paricalcitol. Quantitative mRNA expressions were measured by real-time PCR, whereas protein expressions were determined by Western blotting followed by densitometry. Cytoplasmic and nuclear protein expression of the NFκB subunit p65 (Rel A) were determined by Western blotting. Furthermore, the ratio of phosphorylated to non-phosphorylated IκB-α was measured using specific antibodies. Electrophoretic mobility shift assays and a capture ELISA assay were used to assess NFκB transactivation in vitro. In addition, NFκB transactivation was also monitored in HEK-NFκBIA reporter cells using live cell luminometry. Results: Podocytes expressed the receptor for vitamin D. The vitamins did not suppress receptor for AGEs (RAGE) expression; instead, they rather upregulated RAGE. Although vitamin D3 and paricalcitol partly and differentially modified some of the studied parameters, both hormones inhibited AGE-BSA-induced NFκB transactivation, presumably by various mechanisms including the upregulation of IκB-α protein, keeping NFκB sequestered in an inactive state in the cytoplasm. Conclusion: Vitamin D3 or its analog paricalcitol partly prevented AGE-mediated NFκB activation, an important feature of diabetic nephropathy (DN). Whether this in vitro finding is of clinical relevance to prevent/treat DN requires further studies.

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“…AGEs can induce ectopic calcification in vascular tissues (Pugliese et al ., 2015; Wang et al ., 2012). Activation of the receptor of AGE (RAGE) (Wei et al ., 2013) was recently shown to induce hypertrophy in podocytes (Liebisch et al ., 2014) and calcification in smooth muscle cells (Wang et al ., 2013b). However, the cellular microenvironment in IVDs is very different from that in more highly vascularised tissues, thereby requiring further investigation.…”

Section: Introductionmentioning

confidence: 99%

AGEs induce ectopic endochondral ossification in intervertebral discs

Illien-Jünger

Torre²,

Kindschuh³

et al. 2016

eCM

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Ectopic calcifications in intervertebral discs (IVDs) are known characteristics of IVD degeneration that are not commonly reported but may be implicated in structural failure and dysfunctional IVD cell metabolic responses. This study investigated the novel hypothesis that ectopic calcifications in the IVD are associated with advanced glycation end products (AGEs) via hypertrophy and osteogenic differentiation. Histological analyses of human IVDs from several degeneration stages revealed areas of ectopic calcification within the nucleus pulposus and at the cartilage endplate. These ectopic calcifications were associated with cells positive for the AGE methylglyoxal-hydroimidazolone-1 (MG-H1). MG-H1 was also co-localised with Collagen 10 (COL10) and Osteopontin (OPN) suggesting osteogenic differentiation. Bovine nucleus pulposus and cartilaginous endplate cells in cell culture demonstrated that 200 μg/mL AGEs in low-glucose media increased ectopic calcifications after 4 d in culture and significantly increased COL10 and OPN expression. The receptor for AGE (RAGE) was involved in this differentiation process since its inhibition reduced COL10 and OPN expression. We conclude that AGE accumulation is associated with endochondral ossification in IVDs and likely acts via the AGE/RAGE axis to induce hypertrophy and osteogenic differentiation in IVD cells. We postulate that this ectopic calcification may play an important role in accelerated IVD degeneration including the initiation of structural defects. Since orally administered AGE and RAGE inhibitors are available, future investigations on AGE/RAGE and endochondral ossification may be a promising direction for developing non-invasive treatment against progression of IVD degeneration.

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Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression

Cited by 21 publications

References 68 publications

AGE-Induced Suppression of EZH2 Mediates Injury of Podocytes by Reducing H3K27me3

AGE-Induced Suppression of EZH2 Mediates Injury of Podocytes by Reducing H3K27me3

Vitamin D3 Partly Antagonizes Advanced-Glycation Endproducts-Induced NFκB Activation in Mouse Podocytes

AGEs induce ectopic endochondral ossification in intervertebral discs

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Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression

Cited by 21 publications

References 68 publications

AGE-Induced Suppression of EZH2 Mediates Injury of Podocytes by Reducing H3K27me3

AGE-Induced Suppression of EZH2 Mediates Injury of Podocytes by Reducing H3K27me3

Vitamin D3 Partly Antagonizes Advanced-Glycation Endproducts-Induced NF&#x03BA;B Activation in Mouse Podocytes

AGEs induce ectopic endochondral ossification in intervertebral discs

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Vitamin D3 Partly Antagonizes Advanced-Glycation Endproducts-Induced NFκB Activation in Mouse Podocytes