Glycative stress and glyoxalase in kidney disease and aging

Inagi, Reiko

doi:10.1042/bst20140007

Cited by 21 publications

(16 citation statements)

References 9 publications

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“…WT expression)) for each of these functional categories of activity it was evident that a profound inhibitory activity towards ‘clock regulation’ was present in the input dataset (Figure S6B). Inspection of the individual transcripts coherently regulated across ILN/MLN/ spleen/thymus in GIT2KO mice demonstrated that, aside from the expected changes in immune-related factors (Btla [79], Tnfrsf4 [80], AI467606 [81]), there were significant reductions in multiple clock-related transcripts that are also associated with premature aging and DNA damage repair actions (DDR) (Per1 [22], Per2 [48], Tef [82], Dbp [83], LOC100044862-Fbxl3-like [84] as well as transcripts related to age-related stress/metabolism alterations and cell senescence (Glo1 [85], Ndufb10 [86], Ddit4 [87], Sin3a [88], Rnase4 [89] (Figure 7C). In addition to our LSI-based interpretation of the systemic effects of GIT2 genomic deletion we also individually annotated each significant GIT2KO dataset (ILN, MLN, spleen, thymus) using Ingenuity Pathway Analysis canonical signaling pathways (ILN Table S15; MLN Table S16; spleen Table S17, thymus Table S1).…”

Section: Resultsmentioning

confidence: 99%

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

Siddiqui

Lustig²,

Carter³

et al. 2017

Aging

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Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of ‘neurometabolic’ integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2−/− mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2−/− (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical ‘organ’, i.e. ‘parathymic lobes’. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe – suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature ‘aging’ phenotype of GIT2KO mice.

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Section: Resultsmentioning

confidence: 99%

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

Siddiqui

Lustig²,

Carter³

et al. 2017

Aging

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“…In CKD, it has been reported that renal tubular damage is correlated with a decrease in the activity of glyoxalase I in proximal tubule cells . Similar to the findings of previous research, MG was negatively correlated with eGFR in the present study and remained a predictive factor for outcomes in patients with CKD after adjusting for eGFR and other confounding factors.…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal as a prognostic factor in patients with chronic kidney disease

et al. 2019

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Aim Advanced glycation end products and their precursors cause vascular damage through oxidative stress. We investigated the hypothesis that methylglyoxal (MG), 3‐deoxyglucosone (3‐DG) and pentosidine influence outcomes of chronic kidney disease (CKD) patients. Methods We conducted a 3 years prospective observational study involving 150 outpatients at CKD stages 3–5. At enrolment, MG, 3‐DG and pentosidine plasma concentrations were measured; patients were divided into tertiles according to the concentration of each substance. The primary endpoint was death, a cardiovascular event or end‐stage renal disease. Survival analysis was performed using the Cox regression model. Results The patients’ mean age was 62 ± 12 years, 97 were men, and 20 had diabetic nephropathy. The mean estimated glomerular filtration rate was 25.0 ± 12.1 mL/min per 1.73 m2, which negatively correlated with MG but not with 3‐DG and pentosidine. Forty‐eight patients reached the primary endpoint. Compared with the lowest MG tertile, the hazard ratio for the primary endpoint was 7.57 (95% confidence interval (CI): 1.71–33.54) in the middle tertile and 27.00 (CI: 6.46–112.82) in the highest tertile. When adjusted for characteristics at baseline, the corresponding hazard ratio decreased to 2.09 (CI: 0.37–11.96) and 6.13 (CI: 0.97–38.82), but MG tertile remained an independent risk factor for the primary endpoint. However, 3‐DG and pentosidine were not related to the primary outcome. Conclusion Methylglyoxal has a close clinical association with CKD. Higher MG concentrations may contribute renal function deterioration in CKD. In CKD patients, MG concentration might be useful when determining the prognosis.

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“…Vlassara et al [14] reported that administering AGE-modified rat albumin intravenously resulted in albuminuria and glomerulosclerosis. AGEs are also known to induce vascular calcification and endothelial dysfunction [15,16]. Immunohistochemical studies have shown that AGEs accumulate in the mesangial regions, glomerular capillary walls, and arterial walls of patients with diabetic nephropathy compared to those with healthy kidneys [17,18].…”

Section: Carbohydrate Metabolism and Ckdmentioning

confidence: 99%

“…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

Self Cite

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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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Glycative stress and glyoxalase in kidney disease and aging

Cited by 21 publications

References 9 publications

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

Methylglyoxal as a prognostic factor in patients with chronic kidney disease

Dietary Metabolites and Chronic Kidney Disease

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