Glycative Stress and Its Defense Machinery Glyoxalase 1 in Renal Pathogenesis

Hirakawa, Yosuke; Inagi, Reiko

doi:10.3390/ijms18010174

Cited by 14 publications

(7 citation statements)

References 88 publications

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“…AGE precursors including methylglyoxal and glyoxal are degraded by enzymes, such as glyoxase-1 (Glo-1), and eliminated from the body through the kidney [ 15 , 27 ]. Some previous reports have shown that activation of Glo-1 produces renal protective effects.…”

Section: Carbohydrate Metabolism and Ckdmentioning

confidence: 99%

Dietary Metabolites and Chronic Kidney Disease

2017

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Dietary contents and their metabolites are closely related to chronic kidney disease (CKD) progression. Advanced glycated end products (AGEs) are a type of uremic toxin produced by glycation. AGE accumulation is not only the result of elevated glucose levels or reduced renal clearance capacity, but it also promotes CKD progression. Indoxyl sulfate, another uremic toxin derived from amino acid metabolism, accumulates as CKD progresses and induces tubulointerstitial fibrosis and glomerular sclerosis. Specific types of amino acids (d-serine) or fatty acids (palmitate) are reported to be closely associated with CKD progression. Promising therapeutic targets associated with nutrition include uremic toxin absorbents and inhibitors of AGEs or the receptor for AGEs (RAGE). Probiotics and prebiotics maintain gut flora balance and also prevent CKD progression by enhancing gut barriers and reducing uremic toxin formation. Nrf2 signaling not only ameliorates oxidative stress but also reduces elevated AGE levels. Bardoxolone methyl, an Nrf2 activator and NF-κB suppressor, has been tested as a therapeutic agent, but the phase 3 clinical trial was terminated owing to the high rate of cardiovascular events. However, a phase 2 trial has been initiated in Japan, and the preliminary analysis reveals promising results without an increase in cardiovascular events.

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Section: Carbohydrate Metabolism and Ckdmentioning

confidence: 99%

Dietary Metabolites and Chronic Kidney Disease

2017

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“…Clinical studies have shown that short periods of poor glycemic control might induce irreversible pathophysiological changes in several organs including the kidney, despite subsequent good glycemic control. This phenomenon is called metabolic memory [1,2]. Important mediators for this metabolic memory may be advanced gly-cation end products (AGEs), potentially involved in the dysregulation of epigenetic structures [1,3].…”

Section: Introductionmentioning

confidence: 99%

“…This phenomenon is called metabolic memory [1,2]. Important mediators for this metabolic memory may be advanced gly-cation end products (AGEs), potentially involved in the dysregulation of epigenetic structures [1,3]. The formation of AGEs is caused by hyperglycemia.…”

Section: Introductionmentioning

confidence: 99%

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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“…Multiple factors are involved in the genesis and progression of urological malignancies, including hypoxia, hormone influence, genetic predisposition, oxidative and glycative stresses and inflammation [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. With regards to oxidative stress, glycative stress and inflammation, a complex interplay is known to exist between these biological phenomena, so that each of them fuels the other in a fine-tuned regulatory circuitry.…”

Section: Introductionmentioning

confidence: 99%

Glyoxalases in Urological Malignancies

Antognelli

Talesa

2018

IJMS

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Urological cancers include a spectrum of malignancies affecting organs of the reproductive and/or urinary systems, such as prostate, kidney, bladder, and testis. Despite improved primary prevention, detection and treatment, urological cancers are still characterized by an increasing incidence and mortality worldwide. While advances have been made towards understanding the molecular bases of these diseases, a complete understanding of the pathological mechanisms remains an unmet research goal that is essential for defining safer pharmacological therapies and prognostic factors, especially for the metastatic stage of these malignancies for which no effective therapies are currently being used. Glyoxalases, consisting of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2), are enzymes that catalyze the glutathione-dependent metabolism of cytotoxic methylglyoxal (MG), thus protecting against cellular damage and apoptosis. They are generally overexpressed in numerous cancers as a survival strategy by providing a safeguard through enhancement of MG detoxification. Increasing evidence suggests that glyoxalases, especially Glo1, play an important role in the initiation and progression of urological malignancies. In this review, we highlight the critical role of glyoxalases as regulators of tumorigenesis in the prostate through modulation of various critical signaling pathways, and provide an overview of the current knowledge on glyoxalases in bladder, kidney and testis cancers. We also discuss the promise and challenges for Glo1 inhibitors as future anti-prostate cancer (PCa) therapeutics and the potential of glyoxalases as biomarkers for PCa diagnosis.

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Glycative Stress and Its Defense Machinery Glyoxalase 1 in Renal Pathogenesis

Cited by 14 publications

References 88 publications

Dietary Metabolites and Chronic Kidney Disease

Dietary Metabolites and Chronic Kidney Disease

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

Glyoxalases in Urological Malignancies

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