Hydrogen Sulfide Prevents Advanced Glycation End-Products Induced Activation of the Epithelial Sodium Channel

Advanced glycation end-products (AGEs) are complex and heterogeneous compounds implicated in diabetes. Sodium reabsorption through the epithelial sodium channel (ENaC) at the distal nephron plays an important role in diabetic hypertension. Here, we report that H2S antagonizes AGEs-induced ENaC activation in A6 cells. ENaC open probability(PO)in A6 cells was significantly increased by exogenous AGEs and that this AGEs-induced ENaC activity was abolished by NaHS (a donor of H2S) and TEMPOL. Incubating A6 cells with the catalase inhibitor 3-aminotriazole (3-AT) mimicked the effects of AGEs on ENaC activity, but did not induce any additive effect. We found that the expression levels of catalase were significantly reduced by AGEs and both AGEs and 3-AT facilitated ROS uptake in A6 cells, which were significantly inhibited by NaHS. The specific PTEN and PI3K inhibitors, BPV(pic) and LY294002, influence ENaC activity in AGEs-pretreated A6 cells. Moreover, after removal of AGEs from AGEs-pretreated A6 cells for 72 hours, ENaCPOremained at a high level, suggesting that an AGEs-related “metabolic memory” may be involved in sodium homeostasis. Our data, for the first time, show that H2S prevents AGEs-induced ENaC activation by targeting the ROS/PI3K/PTEN pathway.

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High-mobility group box-1 increases epithelial sodium channel activity and inflammation via the receptor for advanced glycation end products

AJP Cell Physiology ◽

10.1152/ajpcell.00291.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. C570-C580

Author(s):

Garett J. Grant ◽

Theodore G. Liou ◽

Robert Paine ◽

My N. Helms

Keyword(s):

Sodium Channel ◽

Advanced Glycation End Products ◽

High Mobility ◽

Epithelial Sodium Channel ◽

High Mobility Group ◽

Mouse Lung ◽

Advanced Glycation ◽

Open Probability ◽

Glycation End Products ◽

End Products

Cystic fibrosis (CF) lung disease persists and remains life-limiting for many patients. Elevated high-mobility group box-1 protein (HMGB-1) levels and epithelial sodium channel hyperactivity (ENaC) are hallmark features of the CF lung. The objective of this study was to better understand the pathogenic role of HMGB-1 signaling and ENaC in CF airway cells. We hypothesize that HMGB-1 links airway inflammation [via signaling to the receptor for advanced glycation end products (RAGE)] and airway surface liquid dehydration (via upregulation of ENaC) in the CF lung. We calculated equivalent short-current ( Isc) and single-channel ENaC open probability ( Po) in normal and CF human small airway epithelial cells (SAEC) in the presence and absence of human HMGB-1 peptide (0.5 μg/mL). In normal SAECs, HMGB-1 increased amiloride-sensitive Isc and elevated ENaC Po from 0.15 ± 0.03 to 0.28 ± 0.04 ( P < 0.01). In CF SAECs, ENaC Po increased from 0.45 ± 0.06 to 0.73 ± 0.04 ( P < 0.01). Pretreatment with 1 μM FPS-ZM1 (a RAGE inhibitor) attenuated all HMGB-1 effects on ENaC current in normal and CF SAECs. Confocal analysis of SAECs indicates that nuclear size and HMBG-1 localization can be impacted by ENaC dysfunction. Masson’s trichrome labeling of mouse lung showed that intraperitoneally injected HMGB-1 significantly increased pulmonary fibrosis. Bronchoalveolar lavage fluid from HMGB-1-treated mice showed significant increases in IL-1β, IL-10, IL-6, IL-27, IL-17A, IFN-β, and granulocyte-macrophage colony-stimulating factor compared with vehicle-injected mice ( P < 0.05). These studies put forth a new model in which HMGB-1 signaling to RAGE plays an important role in perpetuating ENaC dysfunction and inflammation in the CF lung.

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Enhancement of epithelial sodium channel expression in renal cortical collecting ducts cells by advanced glycation end products

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfl668 ◽

2007 ◽

Vol 22 (3) ◽

pp. 722-731 ◽

Cited By ~ 15

Author(s):

C.-T. Chang ◽

M.-S. Wu ◽

Y.-C. Tian ◽

K.-H. Chen ◽

C.-C. Yu ◽

...

Keyword(s):

Sodium Channel ◽

Advanced Glycation End Products ◽

Epithelial Sodium Channel ◽

Advanced Glycation ◽

Glycation End Products ◽

Collecting Ducts ◽

End Products ◽

Channel Expression

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Advanced glycation end products and oxidative stress as a basis for metabolic abnormalities in patients with type 1 diabetes after successful simultaneous pancreas-kidney transplantation

Terapevticheskii arkhiv ◽

10.26442/00403660.2021.10.201100 ◽

2021 ◽

Vol 93 (10) ◽

pp. 1155-1163

Author(s):

Irina I. Larina ◽

Anastasia S. Severina ◽

Irina S. Maganeva ◽

Alina R. Ainetdinova ◽

Anna K. Eremkina ◽

...

Keyword(s):

Kidney Transplantation ◽

Advanced Glycation End Products ◽

Metabolic Memory ◽

Advanced Glycation ◽

Significant Difference ◽

Glycation End Products ◽

End Products ◽

Pancreas Kidney Transplantation ◽

Simultaneous Pancreas Kidney ◽

Simultaneous Pancreas Kidney Transplantation

Aim. To compare advanced glycation end-products (AGE, RAGE) and 3-nitrotyrosine (3-HT) in patients with DM 1 after successful simultaneous pancreas-kidney transplantation (SPK) and kidney transplantation alone (KTA). To assess relationship between levels of AGE, RAGE, 3-HT and renal transplant (RT) function, carbohydrate and mineral metabolism. Materials and methods. The study included 58 patients who received kidney transplantation in end-stage renal disease (ESRD). 36 patients received SPK. There were performed routine laboratory, examination of AGE, RAGE, 3-NT, parathyroid hormone (PTH), 25(OH)vitamin D, calcium, phosphorus, FGF23, osteoprotegerin (OPG), and fetuin-A levels. Results. All patients after SPK reached normoglycemia (HbA1c 5.7 [5.3; 6.1] %; C-peptide 3.24 [2.29; 4.40] ng/ml) with the achievement of significant difference vs patients after KTA. Arterial hypertension (AH) was more frequent in recipients of SPK before transplantation than after (p=0.008). AH also persisted in greater number of cases in patients after KTA than after SPK. Patients after SPK had higher AGE (р=0.0003) and lower RAGE (р=0.000003) levels. OPG in patients after SPK was significantly higher (р=0.04). The correlation analysis revealed significant positive correlation between 3-HT and OPG (p0.05; r=0.30), RAGE and eGFR (r=-0.52), HbA1c (r=0.48), duration of AH (r=0.34), AGE with HbA1c (r=0.51). Conclusion. The results of the "metabolic memory" markers analysis may indicate their contribution to the persistence of the metabolic consequences of CKD and DM 1 after achievement of normoglycemia and renal function restoration and their possible participation in development of recurrent nephropathy, vascular calcification, and bone disorders.

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