Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction

Sotokawauchi, Ami; Nakamura, Nobutaka; Matsui, Takanori; Higashimoto, Yuichiro; Yamagishi, Sho‐ichi

doi:10.3390/ijms21072604

Cited by 7 publications

(5 citation statements)

References 21 publications

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“…Nevertheless, our study agrees with previous studies demonstrating that AGE accumulation is a predictor of all-cause mortality in CKD [ 34 , 35 ]. Although AGE are mainly considered promoters of glomerular lesion, in vitro and pre-clinical studies suggested a potential role also in tubular injury [ 36 , 37 , 38 , 39 ], but no human studies have explored this issue yet. Therefore, additional studies exploring the associations between AGE and tubular injury markers could be helpful in identifying additional tools for disease monitoring.…”

Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products (AGE) and Soluble Forms of AGE Receptor: Emerging Role as Mortality Risk Factors in CKD

et al. 2020

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Advanced glycation end-products (AGE) can promote chronic kidney disease (CKD) progression and CKD-related morbidities. The soluble receptor for AGE (sRAGE) is a potential biomarker of inflammation and oxidative stress. Here, we explored the role of AGE, glycated albumin, sRAGE and its different forms, cRAGE and esRAGE, as prognostic factors for mortality in 111 advanced CKD patients. The median follow-up time was 39 months. AGE were quantified by fluorescence, sRAGE and its forms by ELISA. Malnutrition was screened by the Malnutrition Inflammation Score (MIS). The Cox proportional hazards regression model was used to assess the association of variables with all-cause mortality. Mean levels of sRAGE, esRAGE and cRAGE were 2318 ± 1224, 649 ± 454 and 1669 ± 901 pg/mL. The mean value of cRAGE/esRAGE was 2.82 ± 0.96. AGE were 3026 ± 766 AU and MIS 6.0 ± 4.7. eGFR correlated negatively with AGE, sRAGE, esRAGE and cRAGE, but not with cRAGE/esRAGE. Twenty-eight patients died. No difference was observed between diabetic and non-diabetic patients. Starting dialysis was not associated with enhanced risk of death. AGE, esRAGE and cRAGE/esRAGE were independently associated with all-cause mortality. AGE, esRAGE and cRAGE/esRAGE may help to stratify overall mortality risk. Implementing the clinical evaluation of CKD patients by quantifying these biomarkers can help to improve patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products (AGE) and Soluble Forms of AGE Receptor: Emerging Role as Mortality Risk Factors in CKD

et al. 2020

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“…AGEs cause tubular damage that progress to DKD. Excess AGEs content leads to oxidative stress [6], inflammation [7], or apoptosis [8] in renal tubules. In the previous study, we had shown the role of AGEs in inducing cholesterol production that is mediated by 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and cholesterol absorption mediated by low-density lipoprotein receptor (LDLr) [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

New insights into the role of empagliflozin on diabetic renal tubular lipid accumulation

Sun

Chen

Hua

et al. 2022

Diabetol Metab Syndr

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Background Glucose cotransporter (SGLT) 2 suppression provides potent renal protective effect during diabetic kidney disease (DKD). This work aimed to explore how empagliflozin (EMPA, the selective and strong inhibitor of SGLT2) affected renal lipid deposition among patients undergoing type 2 diabetes mellitus (T2DM), a T2DM mouse model and human renal proximal tubular epithelial (HK-2) cells. Methods This work divided subjects as 3 groups: non-diabetic volunteers, patients treated with metformin and those treated with metformin plus EMPA. In an in vivo study, EMPA was adopted for treating db/db mice that were raised with the basal diet or the high-advanced glycation end products (AGEs) diet. In addition, AGEs and/or EMPA was utilized to treat HK-2 cells in vitro. Results Results showed that diabetic patients treated with metformin plus EMPA had lower AGEs levels and renal fat fraction (RFF) than those treated with metformin. Moreover, a significant and positive association was found between AGEs and RFF. Results from the basic study showed that EMPA decreased cholesterol level, tubular lipid droplets, and protein levels related to cholesterol metabolism in AGEs-mediated HK-2 cells, kidneys of db/db mice and those fed with the high-AGEs diet. Additionally, EMPA decreased AGEs levels in serum while inhibiting the expression of receptor of AGEs (RAGE) in vitro and in vivo. Conclusion EMPA inhibited the AGEs-RAGE pathway, thereby alleviating diabetic renal tubular cholesterol accumulation.

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“…Some studies have shown that AGEs play important roles in tubular injury during DKD. Excessive levels of AGEs can cause renal tubular oxidative stress [6], inflammatory responses [7], and even apoptosis [8].…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin Alleviates Diabetic Renal Tubular Lipid Accumulation and NLRP3 Inflammasome Activation Through AGEs-RAGE Pathway

Liu

Chen

Sun

et al. 2021

Preprint

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Background: Advanced glycation end products (AGEs) are pathogenic factors of renal tubular lipid accumulation and play a negative role in diabetic kidney disease (DKD). Glucose cotransporter (SGLT) 2 inhibition offers strong renoprotection in the progression of DKD. The aim of the current study was to investigate the effects of empagliflozin (EMPA, a potent and selective SGLT2 inhibitor) on AGEs-induced renal tubular lipid accumulation in both diabetic mice fed with a high-AGEs diet and AGEs-treated cultured human renal proximal tubular epithelial (HK-2) cells. Methods: In vivo, EMPA was used to treat db/db mice fed a high-AGEs diet or an AIN-76 basal diet. In an in vitro study, HK-2 cells were treated with AGEs-bovine serum albumin (BSA) and/or EMPA. Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) translocation was detected by confocal microscopy. Results: EMPA reduced tubular lipid droplets and intracellular cholesterol content, as well as the expression of proteins involved in the synthesis and absorption of cholesterol in the kidneys of basal diet-fed db/db mice, high-AGEs diet-fed db/db mice and AGEs-BSA-treated HK-2 cells. AGEs-BSA loading promoted the formation of SCAP-SREBP-2 complexes and enhanced the transport of the complexes to the Golgi, but these effects were markedly inhibited by EMPA in HK-2 cells. EMPA reduced renal inflammation both in basal diet-fed db/db mice and high-AGEs diet-fed db/db mice, and suppressed NLRP3 inflammasome activation in AGEs-BSA-treated HK-2 cells. In addition, EMPA reduced the serum AGEs level in vivo and inhibited renal tubular endoplasmic reticulum (ER) stress and receptor of AGEs (RAGE) expression both in vivo and in vitro. Conclusions: EMPA attenuated AGEs synthesis and inhibited the AGEs-RAGE signaling pathway, thereby suppressing ER stress and inhibiting abnormal cholesterol metabolism and release of inflammatory cytokines, thus alleviating renal tubular lipid accumulation and inflammation.

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Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction

Cited by 7 publications

References 21 publications

Advanced Glycation End Products (AGE) and Soluble Forms of AGE Receptor: Emerging Role as Mortality Risk Factors in CKD

Advanced Glycation End Products (AGE) and Soluble Forms of AGE Receptor: Emerging Role as Mortality Risk Factors in CKD

New insights into the role of empagliflozin on diabetic renal tubular lipid accumulation

Empagliflozin Alleviates Diabetic Renal Tubular Lipid Accumulation and NLRP3 Inflammasome Activation Through AGEs-RAGE Pathway

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